CA1279868C

CA1279868C - 3-(substituted)propenylaminothiazolylcephalosporanic acids and esters thereof

Info

Publication number: CA1279868C
Application number: CA000511752A
Authority: CA
Inventors: Seiji Iimura; Yoshio Abe; Jun Okumura; Hajime Kamachi; Takayuki Naito
Original assignee: Bristol Myers Co
Current assignee: Bristol Myers Squibb Co
Priority date: 1985-06-24
Filing date: 1986-06-17
Publication date: 1991-02-05
Anticipated expiration: 2008-02-05
Also published as: GB2178032A; YU110086A; FI862642A0; IE861670L; KR930007416B1; DK295386D0; ES556465A0; BE904983A; FR2583757A1; DK295386A; NL8601645A; EG17868A; IT1221767B; GB8615253D0; IL79181A0; CY1618A; NZ216614A; ZA864297B; JPS62491A; KR870000342A

Abstract

3-(SUBSTITUTED)PROPENYLAMINOTHIAZOL-YLCEPHALOSPORANIC ACIDS AND ESTERS THEREOF

ABSTRACT

This invention provides novel cephalosporanic acids and esters thereof having the general formula wherein R2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cyclo (lower) alkyl or acyl, R3 is hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, and R4 is hydrogen, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 5-methyl-2-oxo-1, 3-dioxolen-4-ylmethy}
1-(ethoxyrarbonyloxy)ethyl, or 4-glycyloxybenzoyloxymethyl.
These compounds, especially esters, are useful as broad spectrum antibiotics in the treatment and prevention of infectious diseases of mammals, and for other purposes known in the art.

Description

9~

3-(SUBSTITUTED)PROPENYLAMINOTHIAZOL-YLCEPHALOSPORANIC ACIDS AND ESTERS THEREOF

ABSTRACT

This invention provldes novel cephalosporanic acids and esters thereof ha~ing the general fo~mula .. ~ _ N ~ C - CONH ~ S ~

H2 S oR2 ~ N ~ CH=C~CH2R3 wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cyclo (lower) alkyl or acyl, R3 is hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, and R4 is hydrogen, pivaloyloxymethyl, asetox~methyl, 1-acetoxyethyl, S-methyl-2-oxo-1, 3-dioxolen-4-ylmethyl 1-(ethoxycarbonyloxyJethyl, or 4~glycyloxybenzoyloxymethyl.
These compounds, especially esters, are useful as broad spectrum antibiotics in the treatment and prevention of infec~ious diseases of mammals, and for other purposes known in the art.
Background and Prior Art (A) Published European Patent Application No. 30,630 dis-closes a vast number of 7-acylamino-3-vinylcephalosporanic acid derivatives including, ~nter alia, thoss of the formula N ~ ~ ~ CON~ ~ ~

~2 ~ S ~ OR ~ N ~ C~=C~2 COO~
wherein R inter alia may be (lower)al~yl, ~lower)alkenyl, (lower~alkynyl or carboxy(lower)alkyl. The compounds are pre-S pared, nter alia, by reaction of the corresponding 3~halomethylcompound with a triarylphosphine, followed by treatment with a base and reaction with ~ormaldehyde. Yn each case, the final 3-substituen~ is the vinyl group. There is ~o disclosure or suggestion of a propenyl or a substituted propenyl moiety for the 3-substituent. There is also no dis~losure or suggestion of an ester as pro-drug for oral use referring to the 4-carboxylic acid moiety. That compound wherein R is -CH2CO2H has been refexred to in the literature as FR-027 and as cefvixim.
B~ U~. Patent Specification No. 1,399,086 contains a generic disclosure encompassing a vast number of cephalosporins of the ~ormula B
R-C-CONH - ~

ORa ~ ~ ~p C~O~

-- ~ -~~~ a wherein R is hydroge~ or an organic group, R is an etherifying:
monovalen~ organic group linked to the oxygen through a carbon atom, B i5 _5 or ,S~O, and P is an organic group. In one embodiment, P may be nter alia a vinyl group of the ~ormula ~R3 -C~=C

.' .' .

~ '7~

in which R3 and R4 independently may be hydrogen, nitrile, (lowerl~lkoxycar~onyl, or substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic. HoweYer, the 2-amino-thiazsl-4-yl group is not identified as a possible R substituent and there is no disclosure or suggestion about an ester as pro-drug for oral use concerning the 4-carboxylic acid thereof.
U.S. Patent 3,971,778 and its divisionals Nos. 4,024,133, 4,024,137, 4,064,3~6, 4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 have similar disclosures.

C) U.S. Patent No. 4~307r233 discloses, inter alia, 3-vinyl cephalosporin derivatives of the formula S
I ~ ~ ~ CONH ~ ~ 3 H2N ~ S~ OR ~ N ~ H=CHN \
COo~ R
.

in which R inter alia may be alkyl, vinyl, cyanomethyl or a protective group such as 2-methoxyprop-2-yl, and R3 and R4 are alkyl groups ~optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino~ or phenyl yroups, or R3 and R4, taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of S or 6 members, optionally con-taining another heteroatom selected from N, O and S, and option-ally substituted by an alkyl group. The compounds are useful asintermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There i~ no disclosure or su~gestion of a sub-stituted or an unsubstituted propenyl moiety for the 3-sub-stituent and also no disclosure or suggestion concerning a pro-drug ester for oral use for the 4-carboxylic acid. Published United Ringdom Patent Application No. 2,051,062 is concordant thereto and has a similar disclosure.

D) Published European Patent Application No. 53,537 discloses, inter alia, 3-vinylcephalosporin derivatives of the .

8~3 formula CONH ~ S ~ / R3 ~2N Ra~ \ Rb N ~ CH=C~-N

- in which ~5 and R5 are the same or different and are hydrogen or alkyl, or taken together, form an alkylene group containing 2 or 3 carbon atoms, R5 is an acid protecting group, R2 is an acia protecting group such as an ester, R3 and R~ are the same or different and axe hydrogen, alkyl (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino~ or phenyl groups, or R3 and R~, taken together wi~h the nitrogen to which 10 they ar~ attached, may ~orm a saturated heterocyc~ic ring o~ 5 or 6 members, optionally oont~ining another heteroatom selected from N, O and S, and optionally substituted by an alkyl group~ The compounds are use~ul as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a substituted or an unsubstituted propenyl group for the 3-substituent and an ester of the 4-carhoxylic acid for oral use.

13) U~SO Patent No. 4,307,116 discloses 3-thiovinyl-cephalosporins of the formula - 20 H2N S OR ~ CHSCH-SR
COOH
. .' .' .' '.
in which R is hydrogen, alkyl, vinyl or cyanomethyl, and R inter ~37 alia may be one of a vast number of hetexocyclic rings. There is no disclosure or suggestion o~ a substituted or an unsubstituted propenyl moiety for the 3-substituent and also there is no disclosure or suggestion of an ester thereof for oral use.

5 F) Published European Patent Applieation NoO 53,074 generically discloses a vast number of 3-vinylcephalosporin derivatives of the formula (O) ~ . n la NH~ S ~
N ~ H=C-R3 COOR2a wherein Rla (in one of several embodiments) may be N CCO-H2 ~ ~ ~S

in which R5 inter alia may be hydrogen, alkyl, vinyl, cyano-methyl, an oxime-protecting group such as trityl, etc., or a group o the formula .

\ ~COOR5 Ra~ ~Rb in which R5 and Rb are the same or different, and may be hydro-qen, alkyl ox, taken together, an alkylene radical of 2 or 3 carbon atoms, and R5 is hydrogen or an acid-protecting radical;
R2a is hydrogen or an acid-protecting radical such as methoxy-methyl;
R (in one of several embodiments) may be a methyl group sub-stituted by a 5- or 6-membered aromatic heterocyclic ring containing a single heteroatom, such as 2- or 3-pyridyl, 2- or 3-thienyl ar 2- or 3-furyl; and R3 is a group of the formula in which R4 may be alkyl, trihalomethyl or optionally substituted phenyl. ~hese compounds are s~ated to be intermediates in the preparation of compounds in which the 3-substituent is a group of the formula R
-CH=C-SR
.
which are stated to have antibacterial activity~ Al~hough this patent includes the possibility of R being a methyl group substituted by an N-containing heterocyclic ring, in both the intermediates and final product tthus giving a heterocyclic-substituted propenyl moiety), the re erence exemplifies R in the intermediates and final product only as methyl and further in both the intermediates and final pro~uct, the propenyl group must contain a second substituent (-03SR4 or -SR respectively). There is no diqclosure or suggestion of an ester thereof for oral use.

: G) Published European Patent Application NoO 53,538 discloses, inter alia, 3-vinylcephalosporin intermediates of the formula (~)n N ~ fi ~ CONH ~

H2N ~ S ~ oR5 ~ N ~ CH=CH-R3 OOH

in which n is 0 or 1, R5 is hydrogen, alkyl, vinyl, cyanomethyl or an oxime-protecting group, and R3 is halogen.

ComPlete Disclosure This application relates to novel cephalosporin deriva-tives which are potent antibacterial agents and some of which may be used may be used orally. More particularly, it relates to compounds of the formula N ~ I ~ ~ CONH ~ S ~ I
R HN S oR2 ~N ~ CH=C~CH2R3 CoOR4 wherein R1 is hydrogen or a conventional amino-protecting group R2 is hydrogen, a straight or branched chain alkyl having 1 to 4 carbon atoms, an alkenyl or alkynyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, cycloalkylalkyl having 3 to 6 ring members and 4 to 10 carbon atoms, or acyl having 2 to 4 carbon atoms, R is hydrogen, lower alkyl having 1 to 3 carbon atoms, lower alkoxy having 1 to 3 carbon atoms, lower alkanoyloxy having 2 to 3 carbon atoms, and R4 is hydrogen or physiologically hydrolyzable ester groups such as acetoxymethyl, 1-acetoxyethyl, pivaloyloxymethyl, 5-methyl~2-oxo-1,3-dioxolen-4-ylmethyl, 1-(ethoxycarbonyloxy)ethyl, or 4-glycyloxybenzoyloxymethyl.

Also included within the scope of the invention are the pharmaceutically acceptable acid addition salts, the metal salts ~when R4 is H) and the solvates (including hydrates) of the compounds of Formula I, which may exist in various tautomeric forms which are also included, e.g. the 2-imino-thiazolin-4-yl form o~ the 2-aminothiazol-4-yl moiety.

In another aspect, this application relates to a process for the preparation of the compounds of Formula I.

B~

-7(a)-In yet another aspect, the present invention provides for a pharmaceutical antibacterial composition comprising an effective amount of a compound of Formula I in association with a pharmaceutically acceptable substantially non-toxic carrier or excipient.
In a further aspect of the invention, the use of a compound of Formula I is described for the treatment of a bacterial infection in a mammal.

.

~8~
As shown in the structural formula, the compounds of Formula I have the "syn" or "Z' configuration with respect to the alkoxyimino group. Because the compounds are geometric isomers, some of the "anti~ isomer may also be present. This invention comprises compounds of Formula I containing at least 90% of the n syn" isomer. Preferably, the compounds of Formula I are ~syn"
isomers which are essentially free of the corresponding "anti~
isomers.

In addition to geometric isomers possible with respect to the alkoxyimino group, the compounds of ~ormula I (and the intermediates VIII, XII, XIII and XIV) also form geometric (cis and trans, or Z and E) isomers about the double bond of the propenyl group at the 3-position. Both the cis (nZ") and trans ("E") isomers of these compounds are specifically included within the scope of this invention.

The pharmaceutically acceptable acid addition salts of Formula I are those in which anion does not contribute signifi-cantly to the toxicity of the salt and ar compatible with the customary pharmaceutical vehicles and adapted for oral or parentexal administration. The pharmaceutically acceptable acid addition salts include the salts of Formula I with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, with organic carboxylic acids or organic sulfonic acids such as acetic acid, citric acid, maleic acid, succinic 2S acid, benzoic acid, tartaxic acid, fumaric acid, mand~lic acid, ascorbic acid, malic acid, methanesulfonic acid, p-toluene-sulfonic acid and other acids known and used in the penicillin and cephalosporin arts. Preparation of these salts is carried-out by conventional techniques involving reaction of Formula Ia with the acid in a substantially equivalent amount.

Those substances of Formula I wherein R4 is hydrogen also form pharmaceutically acceptable metal and amine salts in which the cation does no~ contribute significantly to the toxicity or biological activity of the salt. These salts are also part of the present invention. Suitable metal salts include t7~
_g_ the sodium, potassium, barium, zinc and aluminum salts. m e sodium-br potassium salts are preferred. Amine salts prepared from amines used, for instance, with benzyl penicillin which are capable of forming stabla salts with the acidic caxboxyl group include trialkylamines such as triethylamine, procaine, dibenzyl-amine, N-benzyl-~-phenethylamine, l-ephenamine, N,N'-dibenzyl-ethylenediamine, dehydroabiethylamine, N-ethylpiperidine, benzyl-amine and dicyclohexylamine .

~he physiologically hydrolyzable esters serve as pro-drugs by being hydrolyzed in the body to yield the antibiotic E~ sP. They are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydroly-sis occurs in the blood. Suitable esters are the acetoxymethyl,pivaloyloxymethyl, l-acetoxyethyl, l-pivaloyloxyethyl, 3-phthalidyl, p-glycyloxybenzoyloxymethyl, S-methyl-1,3-dioxacyclo-pent-4-en-2-on-4-ylmethyl and others known in the penicillin and cephalosporin art. The most preferred esters are 1-acetoxyethyl and pivaloyloxymethyl.

The compounds of Formula I may be formulated for oral or parenteral use in a conventional manner using kno~n pharma-ceutical carriers and excipients, and they may be presented in unit dosage form or in multiple dose containers. The composi- ~
tions may be in ~he form of tablets, capsules, solutions, sus-pensions or emulsions. These compounds may also be formulated as suppositories utili~ing conventional suppository bases such as cocoa butter or other fatty materials. ~he compounds may, i~ i desired, be administered in combination with other antibiotics including cephalosporins, penicillins and aminoglycosides.

Whe~ provided in unit dosage forms, the compositions will preferably contain rom about 50 to about 1500 mg of the active ingredient of ~ormula I. The dosage of the compounds of Formula I is dependent on such ~actors as the weight and age of the patient, as well as the particular nature and severity sf the ~'~7~

disease, and within the discretion of the physician.
Howe~er, the dosage for adult human treatmen~ will usually be in the range of from about 500 to about 5000 mg per day, - depending on the frequency and route o administration.
When administered intramuscularly or intravenously to an adult human, a total dosage of from about 750 to ~bout 3000 mg per day, in ~ivided doses, normally will be sufficient.

In the compounds of Formula 1, hydrogen is particularly preferred for Rl, hydrogen, acetyl or methyl for R2 and pivaloyloxymethyl or l-acetoxyethyl for R4. The most preferred.compounds of the invention are listed below, and experimental details for their preparation and characterization follow. Those which are not shown by specific example are readily prepared by anala~ous procedures.

~'~7~8~

1) 7B-[(Z9-2-(2-a3i~o~ izzol-4-yl)-2-(~ethox~A~o~acet~do~-3-~(Z) p~op-~-e~-l-yl~-3-cep~e--4-c~rDoxylic Pcid~

2) l-ecetoxyethyl 7B-[(Z)-2-(2-aninoth~Pzol-4-yl)-2-(metboxyiml~o)acet~ldo]-3-[(Z)-prop-l-e~-l-yl~-3-cephe~-4-cerboxylate~

3) piv~1oyloxy~ethyl 7B-~(Z)-2-(2-a~i~othiazol-~-yl~-2-.(methoxyimlno)acet ~$do]-3-[(Z) prop-l-en-l-yl]-3-cephem-4-carboxylate, 4) 7g~Z)-2-(Z-~m~not~iazol-~-yl)-~-(methoxyi~iio~acet~mido3 3-[(E)-prop-1-eD-l-yl~-3-cephe2-4 carboxylic acid~

5) l-acetoxyethyl 7Q-[(Z)-2-(2 a~inothiazol l1-yl~-2-~ethoxyi~i~o~scetP~ido~-3 ~(E)-prop-l-en-l-yl~-3-cepbe~-4-carboxylate~
_ .

6) pi~aloyloxyQethyl 7B-~(z)-2-t2-aminothi~ol-4-yl)-2-(~ethoxyi~iDo~acet ~ido]-3 [(E)-prop-l-en-l-yl~-3-cephe~ 1i-carbo~ylate~ .

7) 73-~(Z)-2-(Z-a~iDothlazol-4-yl)-2-(~ethoxy~iDo)aceta~ido]-3-[(Z)-but-l-en-l-yl~-3:cephe~-4-~&rboxylic ac ia~

1~ 6~3 3) acetoxymethyl 7B-[(Z)-2-~2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3- E (Z) -but-1-en-1-yl]-3-: cephem-4-carboxylate, 9) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-but-1-en-1-yl]-3-cephem-4-carboxylate, 10) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-but-1-en-1-yl]-3-cephem-4-carboxylate, 11) 4-glycyloxybenzoyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-but-1-en-1-yl]-3-cephem-4-carboxylate, 12) 7B-[tZ)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)ac,etamido]-3-[(E)-but-1-en-1-yl]-3-cephem-4-carboxylic acid, 13) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-but-1-en-1-yl]-3-cephem-4-carboxylate, 14) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-~(E)-but-1-en-1-yl]-3-cephem-4-carboxylate, 15) pivaloyloxymethyl 7B-[(Z)~2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-but-1-en-1-yl]-3-cephem-4-carboxylate, 5 16) 4-glycyloxybenzoyloxymethyl 7B-[(Z)-2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-but-1-en-1-yl]-3-cephem-4-carboxylate, 17) 7B-[(2)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-pent-1-en-1-yl]-3-cephem-4-carboxylic acid, 18) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-pent-1-en-1-yl]-3-cephem-4-carboxylate, 19) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-lS (methoxyimino)ac2tamido]-3-[(Z)-p0nt-1-en-l~yl]-3-cephem-4-carboxylate, 20) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-pent-1-en-1-yl]-3-cephem-4-carboxylic acid, .
21~ 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-pent-1-en-1-ylJ-3-cephem-4-carboxylate, ~ ~e ~ 3 ~3~f;?i 22) pivaloylozymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)-acetamido]-3-[(E)-pent-1-en-1-yl]-3-cephem-4-carboxylate, 23) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-3-methoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid, 24) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-3-methoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 25) pivaloyloxym~thyl 7B-[(Z)-2-~2-aminothiazol-4-yl)-2-`~ (methoxyimino)ace-tamido]-3-[(Z)-3-methoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 26) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-3-methoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid, 27) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-30[(E)-3-methoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 28) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-~(E)-3-methoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, , ~
~-J

2~) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylic acid, 30) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-i~cephem-4-carboxylate, 31) pivaloylozymethyl 73-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, ., , ' 32) acetoxymethyl 7B-[IZ)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido-3-[(Z)-prop-l-en-1-yl]-3-cephem-4-carboxylate, 33) 7B-l(Z~-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylic acid, 34) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-prop-l-en-yll-3-cephem-4-carboxylate, 35) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-prop-l-en-1-yl]-3-cephem-4-carboxylate, 36) pivaloyloxymethyl 7B-~(~)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-aarboxylate, 37) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-l-yll-3-cephem-4-carboxylic acid, 38) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido~-3-[(Z)-3-acetoxyprop-1-en-l-yl]-3-cephem-4-carboxylate, 39) 1-acetoxyethyl 7B-~(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-3-aaetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 40) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-: (hydroxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-; 1-yl~-3 cephem-4-carboxylate, 41) 7B-E(Z)-2-(2-aminothiazol-4-yl~-2-(hydroxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid, 42) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-: 1-yl]-3-cephem-4-carboxylate, 43) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 44) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 45) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-E(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid, 7~

46) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 473 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-acetoxyprop-1-en-1-yl]-3-cephem--4-carboxylate, 48) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothia~ol-4-yl)-2-(methoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 49) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-: 1-yl]-3-cephem-4-carboxylic acid, 50) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-ylJ-3-cephem-4-carboxylate, 51) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-~ (methoxyimino)acetamido]-3-[(E)-acetoxyprop-1-en-1-I yl]-3-cephem-4-carboxylate, , 52) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 53) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyamino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylic acid, 54) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 55) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[~Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 56) pivaloylozymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)aceta~ido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 57) 5-methyl-2-oxo-1~3-dioxolen-4-yl-methyl 7B-[(Z)-2-(2-aminothiazol--4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 58) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylic acid, 59) acetoxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylate, .~

~.~7~3~6~

60) 1-acetoxyethyl 7B-[(Z~ -2-(2--aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 61) pivaloyloxymethyl 7B-[(Z)- 2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylate, : 62) S-methyl-2-oxo-1,3 dioxolen-4-yl-methyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 63) 7B-[ (Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yll-3-cephem-4-carboxylic acid, 64) ac0toxymethyl 7B-[ (Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 65) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acètamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, :
66) pivaloyloxymethyl 7B-[ (Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, ~s~6i~

67) 5-methyl-2-oxo-1,3-dioxolen-1,4-yl-methyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-aoetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 68) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3~[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid, 69) acetoxymethyl 7BO[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acètamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 70) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, 71) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)-acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate, :
72) 5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl~-3-cephem-4-carboxylate, 73) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(isopropyloxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylic acid, ~,,; .~d ~ 9 ~3 6 ~

74) 1-acetoxyethyl 7B-[~Z)-2-(2-aminothiazol-4-yl)-2-(isopropyloxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 75) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(i~opropyloxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, : 76) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(allyloxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-- 10 cephem-4-carboxylic acid, 77) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(allyloxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 78) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-1~ (allyloxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-: cephem-4-carboxylate, 79) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-: cephem-4-carboxylic acid, 80) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, ,.90,~ ~r44 .. 3 ., ~ , " ,. ..

~ ~9~

81) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(ethoxyimi.no)acetamido]-3-[(z)-prop-1-en-1-ylJ-3-cephem-4-carboxylate, 82) 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(cyclopropylmethoxyimino)acetamido]-3-[(Z)-prop-1 en-1-yl]-3-cephem-4-carboxylic acid, 83) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(cyclopropylmethoxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 84) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(cyclopropylmethoxyimino)acetamidol-3-[(Z)-prop-1-en-1-y].]-3-cephem-4-carboxylate, 85~ 7B[(Z)-2-(2-aminothiazol- 4-yl)-2-(propargyloxyimino)acetamido]-3-[(Z)-prop 1 en-1-yl]-3-cephem-4-carboxylic acid, 86) 1-acetoxyethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(propargyloxyimino)-acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, 87) pivaloyloxymethyl 7B-[(Z)-2-(2-aminothiazol-4-yl)-2-(propargyloxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate, `` -24~

(88) (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 7~-[~Z) 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)-aceta-mido]-3-[(Z)-prop-l-en-l-yl] 3~cephem-4-carboxy-late.

(89) l-(ethoxycarbonyloxy)ethyl 7~-~(Z~-2-(2-aminothia-zol-4-yl)-2-(hydroxyimino)-acetamido]-3-[(Z)-prop l-en-l-yl]-3-cephem-4-carboxylate.

The in vitro antibacterial activity of pare~t cephalosporanic acids of Formula I is shown in Table 1 in terms of geometric mean of the Minimum Inhibitory Concentrations (MIC's) which were determined by the two-fold serial agar dilution method in Mueller-Hinton agar against 25 strains of test organisms i~ six groups.

Table 2 shows the mouse blood levels o pro-drug esters of Formula I which were determined after oral administrations.

Table 3 shows the in vivo activity of pro-drug esters of Formula I against S. aureus Smith, B. col~ Juhl, Pr. mirabilis A9900, Pr. ~ A9436 and Ser. marcescens A20019.

Table 4 shows the urinary recovery of various esters.in the mouse.

a31e 1 In itro Actlv~ty c Cephalosporin Acids ~2~S~J 2 ~ ;*C~CB2R3 . OR C~
Geouetric mea~ of MIC (ID~g/~l) _ C~mpound No. GpIa GpTb ~nIa GnIb G~TI
(BMY No. ) * ~.2 ~ t5*) SS) (5) t 29~28232) Z ~ ~1 0.20 0.40 ~.066 0.35 6.3 37~28266) i:}I OAc t).17 0.40 D.02S 0.1 1.1 53(28270) Z Ac ~ Q. 17 0.40 0.057 0.26 3.6 . . . .

01(2~098) Z ~s El 1 .~ 3.6 O. 1 0.52 ~.3 4(28252) EC~!~ B 204 3.6 0.3 0.91 8.4 7~28156,) Z~:EIs ~1~ 1.8 3.1 ~1.30 0.80 6.3 12~2~204~ ' E C~J ~ BI 1.8 4.1 0.65 . 1.8 14 17(28215) Z Ci~ C~2C~19 1. 1 1 .6 9.53 ,~.2 :~.2 15 20(28217) E Cl~ C~ 1.2 ;!.4 0.46 0.91 6.3 45~28248) Z CH~ . OAe 1.2 1.6 0.05 0.15 0.~1 49(28280) E C~ . OAc 0.53 1.6 0.025 0.087 0.6 23(2815~) ZCE~3 OC~ . 2.1 2.4 ~.10 1:~.35 S.S
79~2~2 5) Z~EI2~1g ~ . 2.1 3.1 0.30 ~.91 7.3 .
20 73(28233) ZCB(C~I~) 2 ~ 1.6 2.7 0.53 1.2 8.3 76~2~234) ZC~32C~ 2 8 1.4 1.8 /:~.3~ 1.0 ~.3 85 28237 ZCE~2~1 E[ 1.4 ~.6 0.23 O.9l 14.9 82428236) Zt~2~ O~S 1.6 0.~0 1.2 ~.3 Cefadr~x~l l.4 3.6 8.3 17 ~10~
2C Cefaclor 0.7 4.7 0.92 11 ~100 .

Cefvix~l) 4.7 12.5 0.016 3.1 3.2 (F}~-027 ) . .
C-?~ Penicillin (PC~ -sensiti~e S. 2ure~s G~I~: PC resistznt S. zureus S G-r.-Iz: Ce~h210~nin(CET)-s2nsî'i~e E. c~li (2 strains~, K.
eumo~i2e (1) ~G P. mi~zbilis (2) Gn-Ib: C~-resist~nt ~:. c~ 3) znd R. pneumon:!2e ~2) Gil-TI: 1~. morcznii (1), E_ clozc2e (2) a~d S. ma~cescens ~23 1 ) ~ ~ IC ~ CON~; ~ 5~
1~2N~ N~ ~L
O~COO~
~00 ~''' , .

. .
;~

~ ~779~3~B

~81 e '~
`'c~:s~_lood Lev~ls o' ?.-Q~ 2~

2~ 5 ~Cl~2 ~L N ~c~l~cllcll2n3 co~ 4 lûO ~e/k~. po ~ 20 ~:g/kR~ p ._ ~j ComPound No. C~ 2 AUC C~ ~ 1/2 _ ~BIilY NO! ) R2 R~ R~ t hr/~l) tn~ 8 Hr/

(;28271 ) ~ S) 2 36 1.3 61 9~9 1.0 16 39 (282~ 0Ae ~S Z
!;S (2825a ) AC H ~ 2 27 0.8 ~0 7.6 0.8 9.4 3 (-28099 ) C%~ I) Z 33 2.2 - ~6 ~ 2.6 18 2 (28191 )~J ~ S Z S~ 2.3 118 21 1.9 37 5 ~282SS ) ~ ~ ~ E
(28155 )C~ rV 2 21 3.0 S1 5.7 4.D 1~, 8 (-2822S )Cfil C~J A!12) ~ lS

9 (28170 ) CB~ CHa AX ~ 43 1.55t 5.0 0.80 7.1 11 (28231 )CH~ C~s C~") Z S.b2.30 13 14 ( 2E20S ) C~ J~ E SS 7.0 69t 12 13 239 18 ( 28216 )C~J C~2C~3 ~ Z 46 2.S 98 9.11.~ 22 .
(l2a1$8 )C~ ~ Z ~S 2.3 27 3.3 1.7 6.~
24 (281~ Z 1S l.1 21 ~i.3 1.3 6.2 Ce~C1O~ 26 I.23S ~.S 0.91 - ~.9 Ce~V~X~ 28 1.675 10 1.5 2S
CeOd~X~1 S7 1.6 69 12 1.4 16 - 1) PV - -C~320C0C~CH
2) ~ - _CH20CDCH9 3~ -CH tCH ~) DCD~1 ~) CEH - -C~DC/~OCOCI1~NH~

..
~; Ta~ 1~ 3 d In vi~ A~ti~ty of Pro-Drug Esters i~ M~ce ~ D~D (~/k~, p~ S. ~arcr~-S ( MY ~0. ~ SmichE. colil~ill5 19436 ~20019 .

( 28258 ) ~ .36 3 ( 28D99)6.3 4.5 2 ( 28191)8.5 1.6 ( 28155)7-~ . 3-4 3-4 ' 0 55 2.6 10~ ( 2~225)11 ( 28170~6.3 1.7 2.7 ~0O39 3.6 11 ( 28231)~25.
14 ~ ~8205~11 ( 2~1~8)~.1 1524 ( 28171)22.5 . ..
Cefaolor0;35 0.63 3.0 3.1 ~ 25 Cef~x~~ 25 1.6 . 1.2 D.68 1.1 Cef adro~ 13 - - -.

,. . . .

.

- ~ ~`7 ~ 8 . Table 4 Mouse Urinary Recovery of Oral Pro-Dru~ Esters Dose _ ~ Recovery omp~und~/kq, Po? 0-2 hr 2-4 4-6 6-24 Total BMY-28170~100 17 6.3 2.2 3.5 29 _~lot 2~ -13 4.0 1.1 1.6 19 FK-027 100 2.9 9.1 6.9 6.5 25 B-S io86 lot 2j 2.8 4.1 372 2.9 13 Assay standard a: BMY-28154 ' 10 ., h__cefurDxLme__ Another aspect of this invention ~elates to processes for the preparatio~ of the compounds of Formula I. The preferred procedures are shown below ir. Reaction Schemes 1 and 2. In these reaction schemes the abbreviation Ph represents the phenyl group.
Thus, the CH tPh) 2 moiety is the benzhydryl or diphenylmethyl group which is a preferred carboxyl protecting group. The abbreviation Tr mea~s the trityl or triphenylmethyl group which is a preferred amino protecting group. R2a i~ a conventional protecting group used in cephalosporin chemistry with respect to hydroxy groups and includes trityl, chloroacetyl, formyl, trichloroethoxycarbonyl, tert.-butoxycarbonyl, carbobenzyloxy, .

etc. The defini~ion of R2a also includes those same groups included in the definition of R~ except for hydrogen.

Reaction Scheme 1 shows that the desired 7-side chain acid is introduced in the early stage. Then the group of ~he 3-position is converted to the su~stituted propenyl moiety. On the other hand, in Scheme 2 the 7-amino group of the startins Compound II is protected as a Schi~f's base during most of the reaction ~tage and the desired 7-side chain acid is added later in the synthesis. Deblocking of both VIII and X~V gives ~he 'O parent ~ids Ia which are converted to the pxo drug esters Ib by conventional procedures.

Reaction Scheme 1 shows two alternate means o~ going ~rom Compound IV to Compound VI. On~ i~ the direct route of the reaction o~ the chloro derivative IV with triphenylphosphine ~o give the phosphonium and another is that the chloro derivative is converted to ~he more active iodo Compound V, then ~his i~
reacted with triphenylphosphine to give the phosphonium ~I.
~her~ is no significant di~erence between them in their yields.

Reaction Scheme 2 shows two alternate means of going from Compound XIII to Compound Ia. pne i~ acylation of XIII with 2-aminothiazolyl acid XX to Compound XIY followed by deblocking to Compo~nd Ia, The other is acylation with a thiazolyl acid III
- having 2 N-protected-amino (such as N-tritylamino) group to give Compound VIII which i~ deblocked to Compound I~.

2~ In Reaction Schemes 1 a~d 2, the benzhydryl group was shown as the preferred carboxyl-protecting group. It will be appreciated by ~hose skilled in the art that other carboxyl-protecting groups, well-known in the art, may be used. The acylating acid III or XX may be used in the iorm of a deriva-tive such as its acid halide, activa~ed ester, mixed acid an-hydride, etc., all of which are well known in the art. ~cylating acid ~II also may have its amino group protected by ~ny'of the common amino-pro~ecting groups, e.g. ~-trityl, N-formyl, N-t-butoxycarbonyl or ~he like.

.... ~ .

The base used to convert the phosphonium halide (VI or X) to ~-ive the phosphorylide (VII or XI) may be NaOH, Na2CO3, IRA-410 ~OH ) resin, IRA (CO3 ~ resin, or the lik~, or a mixture thereof. Aeaction of the ylide VII (or XI1 with ~cetaldehyde or substituted acet~ldehyde will give the 3-propenyl derivative VIII
tor XII).

We have ~ound that Comp~und XII from XI ~Scheme 2~
typically had a Z:E ratio of about 3-S:1 at th~ 3-(1-propenyl) configuration, while Comp~und YIII from VII ~Scheme 1) exclusively had the Z configuration. The diffe~ence may not be in the route used, but in the conditions utilized in the Wittig reaction (VII to VIII or XI to XII). We ha~e also f~und that the use of ~n appropriate lithium halide such as lithium chloride, lithium bromide or li~hium iodide in the Wittig reaction caused improvement of the yield and puri~y of the Wittig reaction product VIII (or XII). The reaction i~ preferably carried out with 5-15 equivalents of the li~hium halide. If desired the Z
isomer of.the Compound XIII ~XIII(Z) in ~cheme 3) may be converted to the corresponding ~ isomer (XIII(E~) by 20 photochemical reaction in the presence of a sensitizer. The reaction is usually carried s~ut in a solvent selected from methanol, eth~nol, prc~panol, benzene, toluene, ~cetone, : acetonitrile, dichloromethane, DMF, ethyl acetate, THF, pyridine and ~he like in the presence o~ 0.5 - 10 egui~alent~s) of a 2S ~ensiti2er selecte~ from acetophenone, benzophenone, benzil, naphthalene, ethyl pyru~ate and the like. In the Scheme 3, R4a means hydrogen or benzhydryl~

Debl~sking of VIII (or XIV) t~ Ia is usually carried out with tri~luoroacetic acid (TFA) i~ an adequate solvent in the presence of anisole~ The acid Ia thus obtained was purified by reverse phase column chromatography utilizing a glass column containing the paoking rem~ved from a Waters' A s~ciates PrepPAX-500/C18 cartridge.

~he ester Ib may be prepared in a conventional manner, ~or example ~y reacting the acid Ia or a ~alt thereof (such as *Trade Mark ,, . . .

sodium, p~tassium, triethyla~monium, etc.) with a halogenated compound of the formula R -X

wherein X is chloror bromo or iodo and R4 is a group selected from -CH20COC(CH3)3 , -~OCOCH3 , -CH2-~ CH3 , -CH20COCH3 , 0 ~

-CH ~ C oR OC~ CH o ~0 ~ N~2 The reaction is carried out effectively in an inert organic solvent su h as N,~-dimethylformamide, N,N-~Lmethyl-: 10 acetE~ide, dimethylsulfoxide, acetone, acetonitrile, ~r the like, at a temperature in the range of from -10C ~o +50~C, conveni~nt-ly between 0C and 5CC. The ester Ib thus obtained is purified by conventional column chromatography by using silica yel.

Reaction Scheme 1 ~2N ~ S ~ II

0 ~ ~ C~Cl COOCHPh2 III

CI--CONH;r~

.- COOCE~ph2 Na I or ~I

~C ~ ~ONE~
TrNH S \oR2 ~ ~N ~CH2~ PPh3 COOC~Ph2 ~¦PI~h3 S

S TrNHi~D~LCH2PPh3y OOCHPh2 VI
. -- _ . .. .

~ ¦ base ~1, ;

M~ ~ CONH T~ ~ tTII

TrNH J~s \OR2a ~N ~CH=PPh3 COOCHPh2 1 R3CH2CHo ~:7~

N 1- CONH~ ~
I~N ~ ~ CH=CHCH R
TrN~~~ 5 ~ ~OR2a o~ ~ 2 COOCHPh2 V I I I

1.
N ~ C ON~
N~N\OR2 ~ N ~ =C~CH2 COOB
Ia ~ R X

N ~--CONH~S ~ ;
H2~J~N`O~2 ~N~CH=CHCH2R3 cooPS

, ,, 8~

Reaction Schem~ 2 H2~ S ~ II

o~ N~ C H;2C 1 COOC~Ph2 PhC~HO
:~ ' PhCH=Nrl~ S
0~ ~CH2C
COOCHPh2 ~¦~ PPh3 Ph--C~3=N~f S ~ . X
o~L ~LCH2P(C6~5) 3C
COoCHPh2 ~ase ~

Ph-CH=N~ S ~ XI

o~ ~L CH=PPh3 COOCHPh2 ~'~J79B~

1 ~3c~2c~o PhCJ~ X I I
o~ C~C}~2R3 COOC}~h2 E12N~S ~ XII~
~L N~LcE=t:~c~2R3 COOC~?h2 ~N--I~S,~ Tr~N~
\oR2 ` III .... :
~ - . XX ~ .. ~ ,.,,,,.,.,,~", ,. .
'' '''.

~ CON~
~2N ~OR2 ~ N ~LCH=C~lC~i . . Coc)cHph2 XlV

~FA
~ /

N ~ ~ CON~
2NI~ ~oR2 ~L N ~=~HC~2R3 - COC El Ia ~4-X
.

N ~ CON~
~2N ~ S oR2 N~,~C~I=CHCEI2R3 ~ooR4 Ib 38~ 36~

~2 ~ C~2 CoOR4a ¦ hv/sens~t~zer 3~2~--r S~
oJ~ zR3 ~II (E) ,~COO~I
~R2 ~. ". D~ ~ , CO~a~
~2~J~S \ t) ~ 2R3 X~
oR2 COOR

~ 1 C~O~ ~S.~ :
~2 J~ll o~ 2R3 Ia (E) "_ \o~2 CO~
¦R4 X

c~co~s~
~2 ~~ \ o~L ~C~2~ E) oR2 COOF~
'.~

_39 ~ ~ 7 Example 1 Diphenylmethyl 7-amuno-3-~1-propenyl)-3-cephem-4-carboxylate (XXII, R3-H) - To a solution of diphenylmethyl 7-benzylideneamino-3-[ltriphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate ~XI) 12.9 g, 4 mmoles) in dichloromethane (16 ml) was added 90%
acetaldehyde tlO ml, 0.2 mole). The mixture was stirred at room temperature for 30 minutes, dried over sodium sulfate and concen-trated in vacuo. The residue was dissolved in ethyl acetate (80 ml). To the solution was added isopropyl ether (160 ml) and then silica gel ~25 g). The mixture was gently agitated and iltered to remove the solid. The filtrate was evaporated into dryness in vacuo. ~o a solution of the residue in ethyl acetate (48-ml~ was added a mixture of Girard'~ reagent T (1.34 g, 8 mmoles), methanol (40 ml) and acetic acid (2 ml~. The mixture was stirred at room temperature for 30 minutes and concentrated to ca. 10 ml.
The resid'ue was dissolved in ethyl acetate (100 ml~. The so-lution was washed with aqueous sodium bicarbonate and water, dried over sodium sul~ate and concentrated in ~acuo. The residue was chromatographed on ~ silica gel column ~50 g), which was eluted with 1% methanol in chloroform. The eluate was collected in 18-ml fractions. Fraction Nos~ 22-40 were combined and concentrated to give 718 mg of the 3-propenyl derivative XIII
. (R3~ Yield 44~, E~Z=1/3).

TLC : Rf 0.56 ~silica gel, ethyl acetate).

HPLC*: Retention time (min.) 13.2 and 1506 (relative intensity =
3:1) IR : vmax (KBr) ia cm 1 1770, 1720.

W : ~max (C2H50H) in ~m (E) 21~ (20500), 222 (20800), 266 (~200), 273 (4200), 29.2 ~3800).
NMR ~a 1:3 mixture of E and Z isomers~: ~ (CDCl3) in ppm 1.42 and 1.72 (relative intensity e 3~ both are dd, J=2 and 7 Hz, ?d ~7 ~ 8 ~ ~

CH3), 3 . 37 (ABq, J=18 Hz , 2-H~ and 3. 52 (s , 2-H), 4. 72 (d, J=4 . 5 ~Iz, 6-H), 4.97 ~d, J=4.5 ~z, 7-H), 5.50 (dq, J=7 and 11 Hz, =CH-), 6.06 ~dd, J=2 and 11 Hz, 3~CH-), 6.96 and 7.00 (3:1) (s, -OCE~Ph2), 7. 35 (s, phenyl-H) .

*Packing: Lichrosorb RP-18 (4 x 300 2nm). Mobile phase: C~3CN-H2O (1:1). Flow rate: 2.5 mltmin.

Ex ~e 2 Diphenylmethyl 7-1(Z) -2- (2-aminoth_azol-4-yl)-2-methoxyimino-acetamido]-3~ ro~enyl)-3-cephem-4-carboxvlate (XIV, R2=CH , R`'=H ) A mixture of diph~nylmethyl 7~ ino-3~ propenyl~-3-cephem 4-carboxylate (XIII, R3=H) (3.37 g, 8. 3 ~noles) and 1-[~Z)-2-52-aminothiazol 4-yl)-2-methoxyimin~acetoxy]benzotriazole*
~2.64 g, 8.3 m~les) in T~F (70 ml) was stirrea at ro~m tempera-ture ~os 30 minutes and then evaporated in vacuo. A ~olution of lS the residue in ethyl acetate was washed successively with aqueous sodium bicarbonate and water, dried over ~nhydrous so~ium sulfate and concentrated in vacuo to afford a crude pr~duct, which was dissolved in chloroform and chromatographed on a silica gel column (150 g) with 2~ methanol in C~C13. The desired fractions (TLC:silica gel, Rf 0.49, 1:2 toluene-ethyl acetatel were com-bined and concentrated to yield 1.95 g ~40%~ of XIV (R2=C~3, R3=H~ [a 1:2 mixture of E and Z isomers with respect to 3- tl-propenyl) configuration)~

NMR (a 1:2 mixture of the E and Z isomers): ~(CDC13) in ppm 1.45 and 1.75 (relative intensity 2:1) (both are d, J=7 Hz, C-CH3), 3.42 and 3.53 (2:1) (s, 2-~), 4.02 (s, OCH3), 5.13 (d, J=4.5 Hz), 5.2-6.3 ~m, 7-H and vinyl-~), 6.73 (s, thiazole H), 6.93 ~s, OCHPh2), 7.30 (s, phenyl-H).

*Hoe chst, Japan Kokai 54-95593 (7/28/79) and Ger. Offen 2758000 3C (5/7/79) (Ger. Appl. P2758000.3, 12/24/77).

~L e~ ~79 ~
. ~ .

Example 3 ., l 7-[(Z)-2-(2-Aminoth azol-4-yl)-2-methoxyiminoacetamidol-3-(1-~ropenyl1-3-cephem-4-carboxylic a~id (Ia, R2=CH~, R3-H) Comp~un~ XIV (R2=CH3, R3=~) ~1.9 g, 3.2 mmoles) was treated with trifluoroacetic acid (TFA) ~5 ml) at room tempera-S ture for 40 minutes. ~he n~ixture w~s diluted with isopropyl ether (IPE). The resulting precipitate was collected by filtra-tion, dissolved in formic a~id and passed throu~h a column of ~hP
packing ~sa ml~ of a PrepP~ cartridge (Waters), whi~h was washed with water and eluted with 15~ methanol and 204 methanol succes-sively. Evaporation and ly~philization of 15~ methanol eluate - gave 206 mg ~15%) of the title compound (E/Z=1/17). Estim~ted purity 90% (by HP~C). Mp. ~lR0C (slow d~comp.~.

IR : vmax (XBr) in cm 1 177~, 1660, 1630, 1530.

W ~ AmaX (p~ 7 phosphate buffer) ~n nm t~ 228 (17400), 283 ' 15 (~62~O .

NMR : ~(D20 ~ K2C03) in ppm 1.70 (3~t, d, J=6 Hz, C-CH3), 3.52 (2B~ ABq, J=18 ~Iz, 2-H~, 4.03 (3~, ~, CCH~), 5.28 (lH, d, J=4.5 ~z , 6-R~, 5. 6-6. 2 (3~, m, 7-~ and vinyi~ , 7 . 30 (1~, thiazole-H) .

~L~ : Retention time, 6. 8 minutes (1: 3 methanol-pM 7 phosphate buffer, 1. 5 ml/min. ) Anal. C:alc'd. for C ~ N O 5 1/2~ O: C, 44.44; }I, 4.20;
- 16 17 5 ~ 2 2 N, 16.19; S~ 14.83 ~ound: C, 44,37; ~1, 3.94;
N, 16.18; S, 14.53 *Trade Mark ., ~,~, 3~

Example 4 Pivaloyloxymethyl 7-~Z~ -2- ~2-aminothiazol-4-yl) -2-methoxyimino-acetamido~-3-1 (Z) -l-propenyl~-3-cephem-4-carboxYlate (Ib, R2=CH3, R3GH r R~=PV* ) To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-11-propenyl~-3-cephem-4-carboxylic acid ~Ia, R2=CH3, R3=H) (E~Z=lJ17, 90 mg, 0.21 mmole) and potassium car~onate (44 mg, 0.32 mmole) in DMF (3 ml) was added at 0C
pivaloyloxymethyl iodide ~77 m~, 0.32 mmole~. The muxture was stirred at 0C for 40 minutes, diluted with ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in CHC13 z~nd chromatographed on a silica gel column (silica gel: g) by eluting with 1~ methanol in CHC13 to yield 85 mg (75~) o~ the title compound. Mp. 10~-104C~ Estimated purity 90% (by XPLC).

IR : vm~x ~KBr~ in cm 1 1780, 176~, 168D, 1620.

W : ~max (methanol) in nm (E) 232 (}7800), 287 (13500).

NMR : ~ (CDC13) in ppm 1.23 (9~, s, C(CH3)3), 2.15 ~3H, d, J=7 Hz, CC~3), 3.45 (2H, s, 2-H), 4.05 ~3H, s, OCH3), 5.12 (lH, d, J=4.5 Hz, 6-H), 5.6-6.2 (SH, m, 7-H, vinyl-~ and -OCH20-), 6.85 (1~, s, thiazole~

HP~C : Retention time, 8.1 minutes ~1:1 CH3CN-~2O, 2 ml/min.) *PV: ~CH2OCC~CH3)3 Example 5 1-Acetoxyethyl 7-[~Z)-Z-(2-aminothiazol-4-yl)-2-methoxyimino-, acetamido] -3- [ (Z) ~l-ProPenyl]-3-cephem-4-carboxylate ~Ib, R =CH3, R =H, R =AX* ) To a mixture of 7-[ ~Z3 -2-(2~-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3~ propenyl)-3-cephem-4-carboxylic acid (190 mg, 0.45 ~ole) and potassium carbonate t75 mg, 0.S4 mmole) in D~F (5 ml) was added at 5C 1-bromoethyl acetate~* (90 mg, 0.54 mmole). The mixture was stirred at 5~C for 1.5 hours and diluted with ethyl acetate (20 ml). The dilute was wash~d successively with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium ulfate and concentrated in vacuo.
The residue was dissolved in chloroform and chromatograph~d on a silica qel column ~5 g) with 1% methanol in chloroform. The desired fractions were c~mbined and concentrated. ~he residue was dissolved in dioxane and lyophili~ed to yield 103 mg (45~) of the title compound as its dioxane solvate. Mp. 105-110C.
Estimated purity 854 (by HPLC).

IR : vm2x tKBr) in cm 1760(br.) 9 1670, 1610.

~max (ethanol) in nm (E) 233 (15700), 292 1128~0).

NMR : ~ (CDC13) in ppm 1.50 (3H, ~, J=6 Hz, OCHCH3), 1.65 (3H, d, J=7 Hz, =CH-CH3), 2.07 ~3H, e~ COCH3)~ 3.43 (2H~ s, 2-H3 ~ 3.68 (4H, s, 1/2 dioxane), 4.05 ~3H~ s, OCH3), 5.10 (lH, d, J=4.5 Hz, 6-~), 5.5-6.0 (2~, m, 7~ and =CH-CH3), 6.12 ~lH, d, J=12 Hz, 3-CH=), 6.83 (lHt ~, thiazole-HI, 6.98 (lH, q, J=6 Hz, OCHO).

HPLC : Retention time, 7 .5 minutes (1:1 CH3CN-H2O, 1 ml/min.) *AX = -CH(CH3)OCOCH3 ~*E. Buckley and E. Whittle, Can. J. Chem., 40, 1611 (1962).

36~
.~ ~
--~4--..
Example 6 Diphenylmethyl 7-amino-3-[(Z)-l~butenyl~-3-cephem~4-ca~boxylate hydrochloride (XIII, R -CH3 hydrochloride3 To a solution of propionaldehyde (10.7 g, 18 mmoles) and lithium iodide (13.4 g, 10 mm~les) in DMF~C~2C12 ~50 ml/150 ml) was added XI ~7.3 g 10 mmoles) at 0C. The mixture was allowed to stand at 5C for 2 days and concentrated ln ~acuo. A
solution of th~ residue in ethyl acetate ~200 ml) wa~ washed with water, dried over MgS04 and evaporated ln ~acuo to a syrup, which was treated with CC14 (200 ml~ and filtered. ~he filtrate was concentrated to ca. 50 ml and the concentrate was stirred with 6N
HCl (4 ml) at room temper~ture for 30 minutes. The resulting precipitate was collected by filtration and recrystallized from CHC13-ethyl acetate to yield 1.49 g ~33%~ of the title co~p~und.
Mp. 120 127~C.

IR : vmax ~X~r) in cm 1 1780, 1710.

W : Amax tmethanol) in nm (~) 217 ~13900), 2~6 (7400).

NMR : ~ (DMSO-d6) in ppm ~.93 (3H, t, J=7 Hz, CH3~, 2.00 ~2H, m, CH2CH3), 3.75 (2H, ~Bq, J=16 Hz, 2-H), 5.1-5.9 (3H, m, 6-~ and 7-H, =CH-C~2-~, 6. 33 (lH, d, J=12 Hz, 3-CH~, 6.97 (lH, s, -CHPh2~, 7.40 (lOH, s, phenyl-H).

HPLC : Retention time (minutes) 10.4 and 12.0 (relative intensi-ty = 8:1) (4:1 methanol-p~ 7 phosphate buffer, 1 ml/min.) .

8~

Example 7 ., Diphenylmethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2~methoxyimino-acetamido~-3-[(~ buteny~-3-cephem-4-carboxylate (XIV, R2=CH3, R3=CH~) . .
S A suspension of diphenylm~thyl 7-~mino-3-[(ZJ-l-butenyl]-3-cephem-4-carboxylate hydrochlsride (1.41 g, 3.1 mmoles) in ethyl acetate (20 ml) was shaken with aqueous NaHC03 to give a clear t~o-laye~ solution. The organic layer was separated, washed with water and then an a~u~ous .~aturated NaCl solution, and dried over MgS04. To the dried filtrate was added l~(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzo-triazole (1.27 g, 4.0 mmoles), and the mixture was stirred at room temperature for 20 hours. The reaetion mixture was ~iltered and the filtrate was washed with aqueous NaHC03, water and a saturated MaCl solution, dried over MgS04 and evaporated in vacuo. The residue was chromatographed on a silica gel column ~40 g) wi~h 3:1 CBC13-ethyl acetate o yield 1~7 g (91%) of the title compound. TLC (silica gel)~Rf 0.25 (1:1 CHC13-ethyl acetate).

IR : vmax (RBr) in cm 1 1780, 1720, 1680, 1620.

W : AmaX (ethanol) in nm (~) 288 (12400).

NMR : ~ (CDC13) in ppm 0.86 (3R, t, J=7 ~z, ~CH3~ 90 (2H, m, CH2CH3), 3~45 ~2H, s, 2-~), 4.06 13H, fi, OCH3), 5.15 (lH, d, J=4.5 ~z, 6-H), 5.45 (1~, dt, J=7 and 11 ~z, -C~-CH2-)~ 6.05 (1~, dd, J=4.5 and 9 Hz, 7-H), 6.17 llH, d, J-ll Hz, 3-CH=), 6.75 (lH, s, thiazole-H), 6.97 (lH, s, CHPh2)~ 7.35 (iOH, s, phenyl-H~, 8.08 ~lH, d, J-9 Hz, CONH~.

~l~7~3~36~3 .
4~

Example 8 7- ~ (Zi ~2- (2-Aminothiazol-4~ 2-methoxyiminoaceta~ido~-3-t ~Z~-1-butenvl]~3-~ephem-4~carboxyli~ acid (Ia, R2~CH , R3=CH ) ~ mixture of diphenylmethyl 7-~Z) 2-(2-aminothiazol-S 4-yl)-2-methoxyiminoacetamido~ 3-[~2)~ utenyl~-3-cephem-4-carboxylate (1.65 g, 2.65 mmoles) and anisole (0.5 ml) was treated with TEA (S ml) at room temperature for 1 hourO The mixture was diluted with IPE. The resulting precipitate*1 was collected by filtration and chromatographed ~ a column of the packing (50 ml~ of a ~repPAR cartridge twaters) with 20-304 methanol to yield 605 mg (52%) of the title compound. Estimated purity 90~ (by HPLC). Mp. ~16DC (grad. dec.).

IR ~ x ~KBr) in cm 1 1760, 1670, 1650, 1620.

: ~aX (P~ 7 phosphate buffer) in nm (~ 232 (16200;, 283 (155~0)~
.. ..
NMR : ~ (D20 + NaHC03J in ppm 1. 00 (3~, t, J=7 Bz, C~3~, 2. 00 (2R , dq , J=7 and 7 ~z , -C~2CH3), 3. 52 ~2~, ABq, J=17 Rz J 2-~
4.02 (3~I, s, OC~3), 5.27 (l~, d, ~=4.5 ~z~ 6-I~), 5.4-6.1 (3~?, m, 7-~l and -CR=CH-), 7.00 (lH, s, thiazole-H), Ana 1. Ca lc ' d for C17 ~1 gN505S2 / 2 N, 15. 69; S, 14 . 36 Found: C, 45.41, EI, 4.23;
Nr 15.35; S, 14.21 *~ Retention t~me (minutes), 5. 0 and 6. 4 (relati~re i~tensi-ty ~ 8:1) (3:7 methanol-pH 7 phosphate buffer, 2 ml/min.,~

3~36~

Example 9 Pival~yloxymethyl ?=~ (Zl -2- ~2-amlnothiazol-4-yl) -2-methoxyimino-a etamido~-3-[ (Z?-l-butenyl~-3-cephem-4-carboxYlate (Ib, R2=CH}, R =C~ , R =~V* ) Pivaloyloxy~nethyl iodide ~162 mg, 0. 67 ~T~nole~ was added at O'C to a mixture of 7- [ (~) -2- 12-aminothiazol-4-yl) -2-methoxy-iminoa~etarnidol ~3- [ ~Z) -1 butenyl~ -3-cephem-4-carboxylic acid (197 mq, 0.45 rmnole) and R2CO3 ~93 mg, 0.67 n~ole) in DMF (4 ml). The mixture was stirred at 0-5~C for 1 hour and diluted with ethyl acetate t30 ml). The dilute was washe~ with water and a saturat-ed NaCl solution, dried over anhydrous ~5gS04 and evaporated in acuo. The residue was chromatographed on a silica qel column (5 g) with 14 methanol in CHC13. The desired fractions were com-bined and concentrated in vacuo. The residue waC dissolved in 1~ . dioxane and lyophilized to afford 242 mg (974) of the dioxane solvate of the title compound. Silica yel TLC:Rf D~25 ~1:1 C:E}C13-ethyl acetate). Estimated purity 8596 lby ~IPLC). Mp.
9 0--95 C:.

IR ~ ax (RBr) in cm 1 1780, 1750, 1670.

W A~aX (ethanol~ in nm (E) 233 (15300), 2B5 (11300).

NMR : ~ (CDC13) in ppm 0. 97 ~3H, ~, J-7 ~z CE~2CR3), 1.23 (9H, s, C(CE~3)3), 2.03 ~2~1, dq, J=7 and 7 Hz, --CR2CH3), 3.43 (2~, s, 2-H) , 3 . 67 ~4I~, s, 1/2 dioxane), 4. 02 (3B, s, C)CE~3~ , 5. 10 (lEI, ~, J=4 . 5 Bz , 6-H~, S . 3-6 . 3 (5H, m, 7-B, -CH=Cl~- and -OCE120~), 6 . B2 ~5 ( 1~, s, thiazole-l~), 7. 9? (lH, d, J=8 Bz , CONE~ .

HPLC: Retention time, lO.C minutes (1~ 3CN~;2O, 2 ml/min.) Anal. Calc'd. for C23H29N50752- 1/2C4~O2: C, 50.41~ }~, 5.5B;
N, 11.76; S, 10.76 Found: C, 49.94; E~, 5.57;
N, 11.56; S, 10.76 -4 8~ J~8~B

* PV = -CE120COC ( C~3 ) 3 Example 10 l-Acetoxyethyl 7- ~ (Z) -2- ~?-aminl~thiazol-4-yl~ -2-methoxyimino-acetamido]-3-1 (Z) ~1-butenyl]-3-cephem-4-carboxylate (Ib, R2=CH
~; R =CH~, R =AX* 1 To a mixture of 7-[ (Z) -2- (2~aminothiazol-4-yl)-2-methoxyiminoacetamido~-3-[(Z)-l-butenyl]-3-cephem-9-cArboxylic acid (1.55 g, 3.54 mmoles) and K2CO3 (636 mg, 4.6 mmoles~ in DMF
(4 ml) was added at 5C l-bromoethyl acetate ~769 mg, 4.6 O mmoles). ~he mixt~re was stirred at 5~C for 1 hour, diluted with ethyl acetate (300 ml~, washed with water, dried ~ver anhydrous MgS04 and concentrated in acuo. The residue was diss~lved in chlorofonm and chrom~tographed on a silica ~el column ~50 g) with 1~ methanol in CHC13. The desired fracti~ns were combined and L~ concentrated to a small ~olume. The residue was tritura ed with isopropyl et~er to give 1.29 g (70%) of the title compound as the isopropyl ether solvateO Estimated purity 90~ ~by ~PLC). M~.
103-110DC (dec.).

IR : ~max (XBr) in cm 1 1770~br.) t 1670, 1620.

W : Am~ (ethan~l) in nm (E) 233 (14300), 288 (11000).

NMR : ~ (CDC13) in ppm l.D0 (3~, t, J=7 ~z, -CH2C_3), 1.12 ~12H, d, J=6 ~z, isopropyl ether CH3), 1.53 (3~, d, J-5 ~z, OCHCH3), 1.95 (2~, ~, C~2C~3), 2.0B l3~, s~ COCH3), 3.43 (2B, 6, 2-~), 3.62 (2H, m, isopropyl ether C~), 4.08 (3~ C~3)~ 5.13 (1~, d, J=4.5 H2, 6-B), 5.2-6.2 (3~, m, 7-B and -CH=C~-), 6.87 (lH, s, thiazole-H), 7.00 (1~, g, J~5 Hz, -CHC~3).

HP~C : Retention time, 10.8 minutes (1:1 CH3CN~2O, 1 ml/min.) . .' . :

-49- ~J~
Anal. Calc~d- for C21~2~N50~S2 C6H14 N, 11.19; S, 10.25 .
Found: C, 51.62; H, 6.07;
~, 11.1~; S, 1~.05 *AX = -C~(CH3)0COC~3 Diphe~ylme~yl 7-r~Z)-2-methoxyimino-2-~2-tr;tylaminothiazol-4-yl) acet2lTido~ -3- t (Z~ -3-methoxy~l-propenylJ-3-cephem-4-carhoxylate (vII I, R2aeCH , R3=oCH
3 .-3_ ~
A solution of diphenylmethyl 7- ~ (Zl -2-methoxyimino-2-( 2-tritylaminothiazol-4-yl 1 acetamidoJ -3-triphenylphosphonio-me~hyl 3-cephem-4-carboxylate i~dide (1.19 g, 1 n~ole) in ~'H2C12 (30 mll was shake~ with lN NaO~ ~5 ml) for 2 minutes. The organic layer was separated, washed with wa~ex and a sa~urated 15 agueous NaCl solution, dried o~er anhydrous sodium sulfate a~d . Iiltered. To the filtrat~ was added i60pxopyl alcohol ll5 ml~
and methoxyacetaldehyde (7~ 41 mg, 10 mmoles~ . The max~ure was stirred at room temperature overnight and evaporated to dryness in va~uo. The residue was dissolved in CEIC13 and chromatographe~
on a silica gel column (20 g) with 1: 20 ~thyl acetate-toluene as eluant to afford 570 mg ~66~) of 'che title eompound.

IR ~max (~3r3 in c~ 1 17759 1720~ 1670, 1525, 1175.

NMR : ~ (CDC13 ~ D20~ ppm 3.24 t3~, s, OC~3), 3.3-3.8 (4~, m, S-~2 and Ot:E~2j, 4.13 (3~I, s, NOC}I3), 5.15 (1~, d, J-4.5 ~z, 6-H), 5.98 (lE~) d, J=4.5 E~2, 7-~1), 6.3 (1~, d, J~ z, ~i~yl~H), 6.8 (lE~, ~, thiazole-~) 9 6.93 (lH, 6, CFIPEI2), 7.1-7.5 ~25H, phenyl-H) .

HPIC : Retention time 13.6 ~inutes (3:1 C~3CN-~20, 1 ml/min.) Example l~

7-~(Z1-2-(2-Aminothiazol-4-vl~-2-methoxviminoacetamido~-3-~(Z)-3-methoxy-1-propenYl~-3-ce~he~-4-c~rboxvlic acid (Ia, ~. __ R'=CH , RJ=OCH ) ~ - 3-A solution o~ diphenylmethyl 7~Z)-2-m~thoxyimi~o 2-~2-tritylaminothiazol~4-yl1acetamido~-3 [(Z)-3-methoxy-l~
propenylj~3-cephem-4-carboxylate (550 mg, 0.64 mmole) in anisole-TFA (0.5 ml/5 ml) was allowed to stand at room temperature for 50 minutes and diluted with isopropyl ether to give a precipitatel which was collected by filtration and washed with IPE. The solid was dissolved in methanol ~nd chxomatographed on a column of the packing (40 ml) of a PrepP~X cartridye (Waters~ with 30~ methanol as eluant to afford 104 mg ~36%) o~ the title compound. Mp.
155-159C ~dec. ) . Estimated purity 90% (by HPLC~ .

i5 ~R : v~ x ~KBr) in Gm l l76F, 1660, 1630, 153Q, 1040.

, ~V : ~ax (methanol) in nm (E) 234 (16Ç001 ~ 287 ~14500).

~MR : ~ iDM50-d6 ~ D20) in ppm 3.l9 l3H, s, OCH3), 3.83 (3~, 8, OCH31, 5.17 (l~, d, J=5 Hz, 6-~), 5.4~5.8 (lH, m, ~inyl~
5.72 tlH, d, J=S Hz, 7-H), 6.27 ll~, d, J=12 ~z, vinyl-H), 6~72 (l~, s, thiazole-~)O

HPLC : Retention tLme 9.6 minutes (1:3 methanol-p~ 7 phosphate buffer, l ml/minO) Anal. Calc'd. for C H N O R O: C, 43.30; ~, 4.4g; N, 14.85;
17 l9 5 6 2 S, ~3.60 Found: C, 43.04; H, 4O09; N, 14.59;
S, 13.~9 ~ .
. . . :

7~38~

Example 13 Pivaloyloxymethyl 7-[(Z)-2~(2-aminothiazol-4-yl)-2-methoxy-iminoacetamido~-3-l~Z)-3~methoxy-1-propenyl]-3-eephem-4-carboxylate (Ib, R2=C83, R3- ~ V) Esterification of 7-~(Z)~2-(2-am~nothiazol-4-yl)~2-methoxyiminoacetamido~-3-[(Z)-3-methoxy-1-pr~penyl]-3-cephem-4-carboxylic acid (226 mg, 0.5 mmole) in a similar manner to that described in Example 9 gave the ~itle compound (97 mg, 34%). Mp~
100-102C. Estimated purity 90% (by HPLC, 1:1 methan~l-pH 7 phosphake buffer), IR : vmax (~Brl in cm 1 1775, 1750, 1670, 1530, 1370r 1120.

W : AmaX (methanol) in nm (~) 232 (16600), 289 (1350dl.

NMR : ~ (DMSO-d6 ~ D20) in ppm 1.18 (9H, ~, 3 x C~3~, 3.19 t3H~ , OC~3), 3.57 ~2~, br., SCH2), 3.85 ~3~, ~, OCH3), 5.23 15. . (1~, d, J=S Hz, 6-~), 5O4-5~9 ~4~, mt 7~~ OC~20 and vinyl~
6.24 (1~, d, J=12 Hz, vi~yl-~), 6.74 (l~t 5, thiazole~

E:xam~le 14 l-Acetoxyethvl 7-[(Z)-2-~2-aminothiazol-4-yl)-2-methox~yimin~-acetamido~-3-[(Z)-3-methoxy-1-propenyl]-3-cephe~-4-carboxylate (~b, R2=CR ~ R3SoCX R4~AX~

Esterification of 7-[(Z) 2-l2-aminothiazol-4-yl)-2-methoxyimin~acetamido~-3-[(2)-3-methoxy-l propenyl]-3-cephem-4-carboxylic ~cid ~300 mg, 0.66 ~mole) with 1-bsomoethyl acetate in a sLmilar manner to that described i~ Example 10 gave the title 2S compound (154 mg, 43%). Mp. 102-105C (de~.). Estimated purity 95~ (by XPLC, 1:1 CX3CN-p~ 7 phosphate buffer).

IR : ~max tKBr) in c~ 1 1775-1760, 1670, 1530, 1375.

W : ~max (methanol) in nm ~E~ 232 (15900), 288 (1300D).

-52~

~MR o ~ (CDC13 + D20) in ppm l . Sl (3H, d~ J=5 Hz, C~C~3~, 2. 07 ~3H, s, COC~31, 3.29 (3~, s, C~20CB3), 3.45 (2~, br., S-C~2), 3.87 (2~, d, J-7 ~z, =CHCH203, 4.04 (3H, s, NOCB3), 5~09 (l~, d, J=5 Hz, 6-~), 5.55-5.9 (l~, m, vinyl-H~, 5.97 (l~, a, J=5 ~z, 7~H), 6.8 (l~, d, J=l2 Rz, vinyl-~), 6,83 ~l~, 5, ~hiazole~
6.97 ~l~, q, ~5 ~z, ~C~C~31.
xam~E~le lS

?- r (~z) -2-(2-Aminothiazol-4-yl)-2-methox~minoacetamido~-3-[(E) l-butenyl~-3-cephem-4-carboxylic acid (Ia, R2=CR~, R3-C~, E
SQmer?

A mixture of tbe diphenylmethyl 7-~(Z)-2-(2-ami~o-thiazol-4-yl)-2-methoxyLminoacetamido~-3-l(Z)-l-butenyl~-3-cephem-4-carboxylate which was obtained in Example 7 (7.~ g, 1.3 mmoles), TFA ~25 ml~ an~ anisole (5 ml) was stirred at 5C for 1 hour and diluted with isopropyl ethex. The xesulting precipitate was collected by filtratio~, dissol~e~ in formic ~cid and puri~
. . fied by preparati~.re ~PLC (Waters, System 500, PrepPA~500~t:18~
with 40 P6 methancil. The eluate was monitored ~y analytical EPLC
2nd grouped in two ~ractions, which were evaporated ~n acuo t~
give 0.94 g of the 2 isomer of I~ (R -C~3, R3=C~3) ~nd l,65 g o~
a mixture of the Z isomer and the corresponding E isomer. The mis~tuxe was dissolved in formic a~id and chromat~graphe~ on a column of the packin~ (50 ml) ~f a PxepP~ cartridge (Waters) with 20-304 methanol to yield 0.22 g ~4%) o~ the ~: is~mer t~-gether with 0.90 g o~ the Z ismer. Estimated purity 90~ (by ). Mp. ~17ûC (grad. dec. ) .
.
IR ~x (XBrj in cm 1 1760, 1~60.

W : Amzlx ~p~l 7 phosphate buffer) in nm ~E) 232 (154ûO), 292 ( lg4 00) .
.
N~R : ~ tD20 + Na~CO3) in ppm 1.~8 (3B, t, J37 Hz, C~2CH31, 2.30 (2H, m, C~2CH3), 3.83 ~2~, s, 2-H)~ 4.15 (3H, s, OC~3), 5.37 _53~
~lH, d, J=5 Hz, 6-8) . 5.92 ll~, d, J=5 Rz, 7-HJ, 5.9-6.4 ~lH, m, =C~C~21~ 5.6b tlR, ~, J=16 ~z, 3~ ), 7.18 (11~, s, thiazole-H).

~PL~: : Retention time 6. 4 minutes (3: 7 methanol-p~ 7 ph~sphate buffer, 2. 0 ml/min. ) Ex amPl e 16 ~ .
1-Acetoxyethy1 7- r (Z1-2- (2-~T inothiazo1-4-y1? -2-methoxyimino-acetemido~-3 1 (E)-l-buter~Y1]-3-cePhem-4-carboxv1ate lIb, R'=ca, 3 4 ~ ~ - - ~ ~

To a mixture o~ 7-1 (Z) -2- (2-aminothiazolo4-y1~-2-methoxyiminoacetamido] 3~ 1-buteny1~-3-cephem-4-carboxy1ic acid (130 mg, 0.3 ~r~nole) and i~2CO3 ~55 mg, ID.~S n~no1e) i~ DMF (2.5 ml) ~as added at 5C 1-bromoethyl acetate (67 mg, 0~ 4 ~n~le) .
. ~he mixtu:ce was stirred at 5C for 1 hour, dilute~ with ethyl acetate t25 m1~, washed successi~re1y with water and an aqueous NaC1 solution, dried over anhydrous MgSO4 an~ conce~atrate~ ~n ..... .vaeuo. ~he residue was di~so1ved in chloroform and chromato-__ _ graphed on a s~ iica ge1 cc~1u~ with 1~ methanol ~n CBC13. The desired fraction5 were combined and concentratea in vacuo ~o yield 77 mg ~494) o~ the title c~mpound. ~stimated puri'cy 9096 ~by ~P~C). Mp. 110-115C,.

IR : vmax (~Br) in cm 1 1760 (br. ), 1670, 1510.

3.~ ~methano1) in nm (E) 232 (15100), 298 (17000~.

(CDC131 in ppm 1. D5 ~3~1, t, J-7 E~z, CEI~C~I3) ~ 1.54 (3~, d, J~6 E~z, C~ICH31, 2.08 [3~ , COC~3), 2.0-2.4 (2~, m, -CH2C~31, 3.57 (2i~, s, 2-~1), 4.05 (3}I, ~, OCEI3); 5.07 ~ , d, J=5 Hz, 6 5. 8-6.3 (2H, m, 7-~ and ~C,~-CEI2-), 6. 86 (1EI, s, t~azo1e-E~), 6. 8-7.1 (2~, m, OCH and 3-C~

HP~: Retention time, 7.7 minutes (1:1 CH3CN-H20, 1.5 min/ml.l 8~

Example 17 Acetoxymethyl 7-~(Z)-2-(2-aminothia~ol-4-yl)-2-methoxyiminoacetamido)-3-~(Zj--l-butenyll-3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = CH3, R4 - CH3~ 3 Z
isomer) To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (300 mg, 0.69 m mole) and K2CO3 (95 mg, 0.69 m mole) in dry D~F (3 ml) was added dropwise at 0'C
a solution of bromomethyl acetate (105 mg, 0.69 m mole~
in dry DMF (0.25 ml) and the mixture was stirred at 0 C
for 15 minutes. To the mixture was added again a solution of bromomethyl acetate (105 mg, 0.6g m mole) in dry DMF (0.25 ml). The reaction mixture was stirred for another 30 minutes and diluted with ethyl acetate (20 ml). The dilute was washed with water and a saturated NaC1 solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was dissolved in methanol and passed through a column of the packing (40 ml) of a PrePAK cartridge (Waters), which was washed with water and then eluted with 50% methanol. The eluate was monitored by HPLC. The desired fractions were collected and evaporated to give 96 mg (27%) of the title compound. Estimated purity g0~ (by HPLC). M.p. 149-152 'C.
IR: vmaX (KBr) in cm 1 1780, 1660, 1535, 1375, 1170, 1045.
UV: ~max (methanol) in nm (~) 231(17000), 289(13100).
NMR: ~ (CDC13 + D2O) in ppm 0.99 (3H, t, J-7.2 Hz, CH3), 2.11 (3H, s, COCH3), 1.75-2.5 (2H, m, CH2CH3), 3.45 (2H, s, S-CH2), 4.05 (3H, s, OCH3), 5.11 (1H, d, J=4.5 Hz, 6-H), 5.81 (2H, s, OCH2O), 5.99 (lH, d, J=4.5 Hz, 7-H), 6.18 (lH, d, J-12 Hz, 3-CH=), 6.76 (lH, s, thiazole-H).

~ ;~7~
- 54 (a) HPLC: Retention time, 6. 3 minutes (3: 2 CH3CN - pH 7 phos phat e buf f er ) .
Anal. Calcd. for C20H23M507S2 1/2H20: C~ 4 4. 66; N, 13. SO; S, 12. 37. Found: C, 46. 51; H, 4. 44; N, 13. 34; S, 12. 25.

~7~3~6f~

Example 18 4-~N-(t-ButQxycarbony~)alycvlox~lbenzoyloxym thYl 7-~(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamidol-3-t(Z)-~k~yll-3-ce~hem-4-carb~xYlate (Ib,_ R2= CH3 R3 = CH3, R4= = BOC-GBM_) A solution of chloromethyl 4-[N-(t-butoxycarbonyl)glycyloxy~enzoate (584 mg, 1.7 m moles) in acetone (10 ml) was stirred with sodium iodide (1.28 g, 8~5 m moles) at room temperature for 6 hr. The separated sodium chloride ~as removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in dimethylformamide (10 ml) and added at -20 C to a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-buten~l]-3-cephem-4-carboxylic acid (437 mg, 1 m mole) and postassium carbonate (207 mg, 1.5 m mole) in dimethylformamide (S
ml). The mixture was stirred at 0C for 1 hr, diluted with ethyl acetate (50 ml), washed successively with 2.0 water and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column (20 g) eluting with 1:1 toluene-ethyl acetate to yield 533 mg (76 %) of the title compound. TLC (silica gel): RfO.16(1:1 toluene-ethyl acetate). M. p. 110-117 C.
IR: vmax(KBr) in cm 1 1770, 1740, 1670.
UV: ~max(methanol) in nm (~) 237(26700), 287(11800).
NMR: ~ (CDC13 + D2O) in ppm 0.90 (3H, t, J=7Hz, CH2CH3), 1.48 (9H, s, C(CH3)3), 2.00 (2H, dq, J=7 and 7 Hz, CH2CH3), 3.43(2H, s, 2-H), 3.98 (3H, s, OCH3), 4.13(2H, s, CH2NH), 5.10 (lH, d, J=4.5 Hz, 6-H), 5.50 (lH, dt, J=11 and 7 Hz), 5.9-6.3 (4H, m, 7-H, vinyl-H and OCH2O), 6.52 (lH, s, thiazole-H), 7.17 and 8.06 (2H each, d, J=8 Hz, benzene-H).
;~BCC ~ M = -CH20CO ~ COCH2NHCOOC(CH3)3 3~

Exam~le 19 4-GlycvlQxybenzoyloxymethyl 7-~( æL~( 2-aminothiazol-4-yl)-2-methoxyiminoacetamidol-3-~(Z)-l-butenvll-3-ce~ham-4-carbox~late dihydrochloride (Ib, R2V= CH3 ~ 3, R4 = GBM* hydrochloride) A mixture of the N-(t-butoxycarbonyl) derivative (349 mg, 0.5 m mole) obtained in Example 18, anisole (3 drops) and 2N hydrochloric acid in ethyl acetate (2.5 ml) was stirred at 5 C for 15 min. The resulting precipitate was collected by filtration and dissolved in methanol (3 ml). After filtration, ethyl acetate (39 ml) was added to the filtrate. The resulting precipitate was collected by filtration to yield 166 mg (46 %) of the title compound. M.p. >160 C(dec.) Estimated purity 90%
(by HPLC).
IR : vmax (KBr) in cm 1 1780, 1745, 1670, 1630.
W : ~max (methanol) in nm ( ) 235(27200), 287(12900).
; 20 NMR : ~(DMSO-d6~) in ppm 0.78 (3H, t J-7 Hz, CH2CH3), 2.00 (2H, m, CH2CH3), 3.52 (2H, s, 2-H), 3.90 (3H, s, OCH3), 4.05 (2H, s, CH2NH), 5.22 (lH, d, J=5 Hz, 6-H), 5.5-6.2 (5H, m, 7-H, vinyl-H x 2 and OCH2O), 6.88 (lH, s, thiazole-H), 7.35 and 8.00 (2H each, d, J=8 Hz, benzene-H) Anal. Calcd. for C27H28N6OgS2 2HC1 1/2H20 : C, 44-63 ; H, 4.30; N, 11.57 ; S, 8.82 ; C1, 9.76. Found : C, 44.60 ; H, 4.34 ; N, 11.13 ; S, 8.46 ; C1, 9.18.
HPLC : Retention time, 5.2 minutes (3:2 CH3CN-H2O, 1 ml/min.) *GBM = -CH20CO ~ ~I2 2 ~,,.,.; ~

6~

Exam~le 20 Diphenylmethyl 7-amino-3~ entenYl)-3-cephem-4-carboxyla~lXIII, R3 = CH2CH31 To a cooled and stirred solution of 8.7 g (0.1 mole) of anhydrous lithium bromide in 50 ml of DMF was added in one portion a solution of 7.3 g (0.01 mole) of the yield (XI) in 250 ml of methylene chloride. To the solution was added 30 ml of n-butyraldehyde and the mixture was stirred at room temperature for 24 hours. After concentrating to 50 ml, the residue was extracted with 300 ml of ethyl acetate. The extract was washed with water and a saturated NaCl solution, and dried with anhydroùs MgS04. Wako-gel (C-100, 10 g) and active carbon (lg) were added. The mixture was filtered and the filtrate was concentrated to 100 ml. To the concentrate was added S g (0.03 mole) of Girard T in 100 ml of methanol containing 5 ml of acetic acid and the mixture was stirred at room temperature for 30 min. After being evaporated to dryness, the residue was extracted with 300 ml of ethyl acetate. The extract was washed successively with water, an aqueous sodium ~icarbonate solution, water and a saturated NaCl solution and dried with anhydrous MgS04. After evaporating to dryness, the residue was chromatographed on a silica gel column (Merck Kieselgel 60, 120 g) by eluting with toluene-ethyl acetate (5 : 1).
The desired fractions collected by monitoring the TLC
were evaporated to dryness to give 1.78 g (41%) of title compound as a foamy solid.
NMR : ~ (cdcL3) IN PPM 0.7-2.0(7H, m, CH2 x 2 & C-CH3), 3.28 (lH, d, J=18 Hz, 2-H), 3.58(1H, d, J=18 Hz, 2-H), 4.75 (lH, d, J=4.5 Hz, 6-H), 5.01 (lH, d, J=4.5 Hz, 7-H), 5.2-5.7 (lH, m, CH=C), 6.12 (lH, d, J-11 Hz, 3-CH=C), 7.00 (lH, 8, CHPh2), 7.2-7.6 (lOH, m, phenyl-H) Trademark -5~-Example 21 Diphenylmethyl_7-~(Z)-2-(2-aminothiazol-4-yl)-2-methoxviminoacetamidol-3-(1-pentenyl)-3-ce~hem-4-carboxylate (XIV ~2 = CH3 R3_= CH2CH3l A mixture of 1.7 g (3.9 m mole) of XIII (R3 =
CH2CH3) and 1.24 g (3.9 m mole) of 1-[(Z~-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]-benzotriazole in 150 ml of ethyl acetate was stirred at room temperature for 20 hours and the mixture was evaporated to dryness. The residue was chromatographed on a silica gel column (Merck Kieselgel 60, 60 g) by eluting with chloroform and 1 % methanol in chloroform suc~essively.
The desired fractions, eluted with chloroform-methanol and monitored by silica gel TLC (1:15 MeOH-CHCl3, Rf 0.50), were collected and evaporated to dryness. The residue was triturated with ether-isopropyl ether to give 1.94 g (85 %) of the title compound, melting at 115-120 C (dec.) IR : vmaX (KBr) in cm 1 1775, 1720, 1670, 1610, 1530, 1380, 1220, 1180, 1030.
VV : ~max tmethanol) in nm (~ 290 (14000).
NMR : ~(CDCl3) in ppm 0.6-2.1 (7H, m, CH2 x 2 &
- CH3), 3.42 (2H, br s, 2-H), 4.04 (3H, s, OCH3), 5.15 (lH, d, J=4.5 Hz, 6-H), 5.3-5.8 (3H, m, CH=C & NH2),` 6.02 (lH, d-d, J=4.S & 8 Hz, 7-H), 6.15 (lH, d, J=11 Hz, 3-CH=C), - 6.80 (lH, s, thiazole, H), 6.98 (lH, 8, CHPh2), 7.2-7.5 (lOH, m, phenyl-H), 8.0 (lH, d, J=8 Hz, NH).

.~
~v~

Exam~le 22 7=~tZ)-2-(2-Aminothiazol-4-vl)-2-methoxyiminoacetamidol-3-JtZ)-1-penterlYll-3-c~phem-4-carb~oxylic acid (Ia, R2 =
CH3, R3 = CH2CH3, Z isomer~
A mixture of 2.5 g (4.27 m moles) oE XIV (R2 = CH3, R3 = CH2CH3), 2.5 ml of anisole and 7.5 ml of trifluoroacetic acid was stirred at room temperature for 10 min and concentrated to 3 ml. ~he residue was diluted with 100 ml of isopropyl ether to give 2 g of trifluoroacetate of the title compound (a 5:1 mixture oE
~ and E isomers). The crude product wa~ dissolved in aqueous methanol and the solution was chromatographed on a column of the packing of PrepPAK C18 cartridge (Waters, 300 ml) by eluting successively with water, 10 %
methanol, 20 % methanol, 30 % methanol and 40 % methanol.
The eluate was monitored with HPLC. The Z isomer-containing fractions of the 40 % methanol eluate were collected and evaporated to dryness and the residual solid was dissolved in methanol and filtered. To the Eiltrate was aaded 200 ml of isopropyl ether and the resulting solid was collected by filtration, washed with isopropyl ether and dried in vacuo over P2O5 to give 695 mg (39%) o:E the product, which was 90% pure by HPLC. M.
p. 150-155 (dec.).
IR : vmax (KBr) in cm 1 1770, 1670, 1630, 1530, 1370, 1180, 1040.
U~ : ~ma~ (pH 7 phosphate bufEer) in nm (~) 229 (16000), 283(15000).
NMR : ~(D2O ~ Na2CO3~ in ppm 1.01 (3H, t, J=7 Hz, CH2CH3), 1.3-1.7 (2H, m, CH2CH2CH3), 2.0-2.3 (2H, m, =CH-CH2CH3), 3.A6 (lH, d, J=18 HZ, 2-H), 3.76 (lH, d, J=18 Hz, 2-H), 4.15 (3H, s, OCH3), 5.38 (lH, d, J=4.5 Hz, 6-H). 5.5-5.9 (lH, n, CH=C), 5.92 (lH, d, J=4.5 Hz, 7-H).
6.09 (lH, d, J=11 Hz, 3-CH=C), 7.16 (lH, s, thiazole-H).

8~

Anal. Calcd. for C18H21~55S2 1/2H20 C, 4.82 ; N, 15.21 ; S, 13.92. Found : C, 46.93, 47.04 ; H, 4.66, 4.71 ; N, 15.00` 15.00 ; S, 13.34, 13.36.
HPLC : Retention time, 9.9 minutes (2:3 MeOH - pH 7 phosphate buffer, 1 ml/min.) 8~

Exam~l e 2 3 7-~(Z)--2~2-Amino~hiazol-4-yl)-2-methoxyiminoacetamidol-3-~(E)-1-pentenyll-3-cephem-4-carboxylic acid (Ia R2 =
CH3 ~ 2CH3 E lSOmer The E isomer-containing fractions of the 40%
methanol eluate (cf. Example 22) were collected and evaporated to dryness to give 455 mg of a mixture of cis and trans isomers ~1:1). The crude product was rechromatographed on a column of the packing of PrepPAK
C18 cartridge (Waters, 300 ml) by eluting with 35 %
methanol and monitoring with HPLC. ~he desired fractions containing the trans isomer were collected and concentrated to 10 ml and lyophilized to give 89 mg (5 %) of the product which was 75 % pure by HPLC. M.p. 180C
(grad. dec.).
IR : vmaX (KBr) in cm 1 1770, 1660, 1630, 1530, 1380, 1040.
UV : ~max (Ph 7 phosphate buffer) in nm ( ) 228(17000), 292(22000).
NMR : ~(D2O + Na2CO3) in ppm 1.05 (3H, t, J=7 Hz, CH2CH3), 1.2-1.8 (2H, m, CH2CH2CH3), 2.1-2.5 (~H, m, =C~-CH2CH2), 3.81 t2H, s, 2-H), 4.16 (3H, s, OCH3), 5.37 (lH, d, J=4.5 Hz, 6-H). 5.91 (lH, d, J=4.5 Hz, 7-H), 5.9-6.3 (lH, m, CH=C), 6.67 (lH, d, J=16 Hz, 3-CH=C), 7.17 (lH, s, thiazole-H).
HPLC : Retention time, 12.3 minutes (2:3 MeOH-pH 7 phosphate buffer, 1 ml/min.).

8~

Exam~le 24 1-Acetoxyethyl 7-~(Z)-~2-(2-aminothiazgl-4-yl)-2-methoxyiminoacetamidol-3-~(Z)-1-~entenyll-3-cephem-4-carboxylate ~Ib, R2 = CH3 R3 - CH2CH3, R4 - AX Z lsomer To a stirred mixture of Ia (R2 = CH3, R3 = CH2CH3, Z
isomer) (225 mg, 9.5 m mole) and 69 mg (0.5 m mole) of potassium carbonate in 5 ml of DMF was added at 0-5 C a solution of 84 mg (0.5 m mole) of 1-acetoxyethyl bromide in 1 ml o~ DMF and the mixture was stirred at room temperature fox 30 min. To the mixture was added again a solution of 84 mg (0.5 m mole) of the bromide in 1 ml of DMF and the mixture was stirred at 5-10 ~C for 30 min.
Then, the mixture was extracted with 100 ml of ethyl acetate. The extract was washed with an aqueous sodium bicarbonate solution,'water and a saturated NaCl solution successively and dried with MgSO~. After evaporating to dryness, the oily residue was chromatographed on a silica gel column (Kieselgel 60, 30 g) by eluting with chloroform and 1 % methanol in chloroform successively, and monitoring with TLC and HPLC. The desired fractions sluting with 1 % methanol in chloroform were collected and evaporated to dryness. The residue was triturated with ether-n-hexane to give 91 mg of the title compound.
The crude side fractions were re-chromatographed similarly to give additional 63 mg o~ the product. The total yield was 154 mg (57%). Est'd purity 80% by HPLC.
M.p. 100-110 C (dec.).
IR : vmaX (KBr) in cm 1 1765, 1670, 1610, 1530, 1380, 1240, 1210, 1180, 1100, 1070, 1040.
UV : ~max (methanol) in nm (s) 233(17000), 290(13000).
NMR : ~(CDC13) in ppm 0.90 (3H, t, J=7 Hz, CH2CH3), 1.2-1.8 (5H, n, CHCH3 & CH2CH2CH3), 1.8-2.1 (2H, m, =CH-CH2CH2), 2.06 (3H, s, COCH3), 3.43 (2H, br-s, 2-H), 4.05 (3H, s, OCH3), 5.08 (lH, d, J=4.5 Hz, 6-H), 5.32 (2H, br ......
~,....

36~

s, NH2), 5.5-5.7 (lH, m, CH=C), 5.94 (lH, d-d, J=8 & 4.5 Hz, 7-H), 6.13 (lH, d, J=ll Hz, 3-CH=C), 6.84 ~lH, s, thiazole-H), 6.97 (lH, q, J=7 Hz, CH-CH3), 7.48 (lH, d, J=8 Hz, NH).
HPLC : Retention time, 8.1 minutes (7:3 MeOH-pH 7 phosphate buffer, 1 ml/min).

Exam~le 25 Diphenylmethyl 7-~2-(2-tritylaminothiazol-4-yl)-2-~Z)-_sopropylox~imino-acetamidol-3-[(Z)-1-~ropenyll-3-cePhem-4-carboxylatç (VIII R2a = CH(CH3)2, R3 = Hl To a mixture of 2-~2-tritylaminothiazol-4-yl)-2-(Z)-isopropyloxy-iminoacetic acid (III, R2a = CH(CH3)2: 754 mg, 160 m moles) and dichloromethane (7 ml) was added - phosphorus pentachloride (332 mg, 1.60 m moles) at -10 C. The mixture was allowed to stand for 20 min at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3-[(Z)-1-propenyl]-3-cephem-4-carboxylate hydrochloride (XIII, R3 = H: 443 mg. 1 m mole) and N,O-bis(trimethylsilyl)acetamide(0.74 ml, 4.4 m moles) in dichloromethane (5 ml) at -10 C. The reaction mixture was allowed to stand for 30 min. at the same temperature and poured into ice-water. Extraction of the mixture with ethyl acetate followed by evaporation of the extracts under reduced pressure gave the crude product as an oil, which was chromatographed on a column of silica gel (eluted with chloroform) to give 419 mg (49%) of VIII (R2 = CH(CH3)2, R3 = H) as an amorphous powder.
IR : vmax (KBr) ~n cm 1 1780, 1720, 1680 * R. Bucourt et al., Tetrahedron 34, 2233 (1978) ` ~7~86~3 Example 26 7-~2-(2-Aminothiazol-4-yl)-2-(Z)-iso~ropyloxyimino-acetamidQl-3-((Z)-1-propenyl)-3-cephem-4-carboxylic acid (Ie. R2 = CH(CH3~2, R3 = H) A mixture of VIII (R2a = CH(CH3)2, R3=H: 400 mg, 0.47 m mole) and 85 % formic acid (2 ml) was stirred for 3 hr at room temperature and to the mixture was addsd hydrochloric acid (0.08 ml). The mixture was stirred for additional 4 hr and evaporated under reduced pressure.
The residue was triturated with isopropyl ether to give the crude product, which was purified by column chromatography on C-18 silica gel (eluent, 30 % aq. MeOH) followed by concentration under raduced pressure to give the title aompound as needles. Yield 70 mg(33%). M.p.
170-175 C (dec.). Est'd purity 90 %.
IR : v.maX (KBr) in cm 1 1760, 1660, 1540, 1380.
UV : ~ma~ (Ph 7 phosphate huffer) in nm (E11 %) 232(370), 284(357).
NMR : ~(D2O~NaHCO3) in ppm 1.50 (6H, d, J=6Hz, i-Pr), 1.76 (3H, d, J=6 Hz, =CH-CH3), 3.65 (2H, Abqf J=18Hz, 2-H), 5.42 (lH, d, J=4 Hz, 6-H), 5.80-6.40 (3H, m, vinyl-H, 7-H), 7.15 (lH, s, thiazole-H).

~7~8~

Exam~le 27 Di~h~nylmethyl 7-~2-(l2-tritylaminothiazol-4-yl)-2-(Z)-allyloxviminoacetamidol-3-f(Z)-1-pro~enyl!-3-ce~hem-4-carboxylate t2) (VIII, R2a = ~H2CH=CH2, R3 = H) To a mixture o~ 2-(2-tritylaminothiazol-4-yl)-2-(Z)-allyloxyiminoacetic acid (III, R2a = CH2CH=CH2) (750 mg, 1.60 m moles) and dichloromethane (5 ml) was added phosphorus pentachloride (332 mg, 1.60 m moles) at -10 C. The mixture was allowed to stand for 20 min at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3-~(Z)-1-propenyl)-3-cephem-4-carboxylate hydrochloride (XIII, R3 = H: 443 mg, 1 m mole and N,O-bis(trimethylsilyl)acetamide (0.74 ml, 4.4 m moles) in dichloromethane (5 ml) at -10-C. The reaction mixture was allowed to stand for 30 min. at the same temperature and poured into ice-water. Extraction of the mixture with chlo~oform and evaporation of the extracts under reduced pressure gave the crude product as an oil, which was chromatographed on a column of silica gel (eluted with chloroform) to give 817 mg (95%) of VIII
(R2a = CH2CH=CH2, R3 = H) as an amorphous powder.
. IR : vmaX (KBr) in cm 1 1780, 1720, 1680.

*R. Bucourt et al., tetrahedxon 34, 2233 (1978) ,., ~., Example 28 7-~2-(2-Aminothiazol~4-vl)-2-(Z)-alloxyiminoacetamidol-3-((Z)-1-propenyl~-_3-cephem-4-carboxylic acid tIa R2 =
CH2CH=CH2~__3 = H
A mixture of VIII (R2a = CH2CH=CH2, R3=H:810mg, 0.95 ; m mole) and 85% formiF acid (2ml) was stirred for 3 hr at room temperature and to the mixtuxe was added hydrochloric acid (0.1 ml). The mixture was stirred for 3 hr and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave the crude product, which was dissolved in a small amount of methanol and chromatographed on a column of C-18 silica gel (eluted with 30% aq. MeOH). The eluate was concentrated under reduced pressure and freeze-dried to give 215 mg (50%) of the title compound as an amorphous powder. M. p. 140 C(dec.). Est'd purity 80%.
IR : vmaX (KBr) in cm 1 1770, 1660, 1620.
UV : ~max (pH 7 phosphate buffer) in nm (E11 %) 232(378), 285(326).
NMR : &(D2O + NaHCO3) in ppm 1.78 (3H, d, J=6 Hz, C~CH-CH3), 3.62 (2H, Abq, J~18 Hz, 2-H), 5.50-6.30 (7H, m, vinyl-H, 6,7-H), 7.18 (lH, s, thiazole-H).

~'~

Example 29 7-l(z)-2-(2-Aminothia~ol-4-yl~2-(z)-ethoxv-iminoacetamidol-3-((Z)-1-~ro~enyl)-3-ce~hem-4-carboxylic acid (Ia. R _= CH2H5 R H) To a solution of (Z)-2-~2-N-tritylaminothiazol-4-yl)-2-ethoxyiminoacetic acid (III, R2a = C2H5) (458 mg, 1.0 m mole) and 1-hydroxybenzotriazole (135 mg, 1.0 m mole) in a mixture of dichloromethane (20 ml) and tetrahydrofuran (7 ml) at room temperature was added dicyclohexylcarbodiimide (210 mg, 1.0 m mole). The mixture was stirred for 80 min, filtered and the filtrate was concentrated to dryness. The re~idue was dissolved in tetrahydrofuran (10 ml) and diphenylmethyl 3-propenyl-3-cephem-4-carboxylate hydrochloride (XIII, R3=H:443 mg, 1 m mole) and sodium bicarbonate (84 mg, 1 m mole) were added. Water (10 drops) was added and the resulting solution was stirred at room temperature for 12 hr. The reaction mixture was diluted with ether and filtered. The filtrate was concentrated to give an oil.
The oil was chromatographed on silica gel (230-400 mesh), eluting with 2:1 hexane-ethyl acetate to give the acylation product (VIII, R2a=C2H5, R3=H) (400 mg). This was, dissolved in formic acid (1.6 ml), stirred vigorously for 60 min and 12 N HC1 (50~1) was added. The mixture was stirred at room temperature for 3 hr, diluted with water (2 ml) and toluene (20 ml) and evaporated at 30 C
to dryness. The residue was triturated with isopropyl ether, the resulting precipitates were collected and washed with isopropyl ether. The solid waa chromatographed on C-18 silica gel, eluting with 3:7 methanol-water to give the title compound as an amorphous solid, 100 mg (23 %), M.p. 158-C (dec.). Est'd purity 90% (based on HPLC).
IR : v max (KBr) in cm 1 3600-2600, 1765, 1660, 1620, 1530, 1385, 1355, 1035.
UV : ~ max (MeOH) in nm () 235(16100), 284(13800).

,.. , ,~
. - , 3~

NMR: ~(D2O ~ NaHCO3) in ppm 1. 45 (3H, t, J=7 Hz), 1. 77 (3H, d, J=6 E~z), 3. 45 and 3. 75 (2H, Abq, J=18 Hz), 4. 40 (2H, Q, J=7 Hz), 5. 40 (lH, d, J=5 Hz), 5. 75-6. 20 (3H, m), 7. 13 (lH, s).

R. Bucourt et al., Tetrahedron 34, 2233 ( 1978) Example 30 7-~tZ)-2-(2-Am1nothiazol-4-yl)-2-c~clo~roylmethoxv=
iminoacetamidol-3-((Z)-1-~ro~enyl)-3-ce~hem-4-carboxYlic ~ CH~3 _3~ al To a 8 olution of (Z)-2-(2-N-tritylaminothiazol-4-yl)-2-cyclopropyl-methyliminoacetic acid (III, R2a=CH~
) (484 mg, 1.0 m mole) and 1-hydroxybenzotriazole (135 mg, 1.0 m mole) in a mixture of dichloromethane (20 ml) and tetrahydro~uran (7 ml) at room temperature was added dicyclohexylcarbodiimide (210 my, 1.0 m mole). The mixture was stirred ~or 80 min, filtered and the filtrate was concentrated to dryness. The residue was dissolved in tretrhydrofuran (10 ml) and diphenylmethyl 3-propenyl-3-cephem-4-carboxylate hydrochloride (XIII, R3=H) (443 mg, 1.0 m mole) and sodium bicarbonate (84 mg, 1.0 m mole) were added. Water (10 drops) was added and the resulting solution was stirred at room temperature for 12 hr. The reaction mixture was diluted with ether and filtered. The filtrate was concentrated to give an oil. The oil was chromatographed on silica gel (230-400 mesh), eluting with 2:1 hexane-ethyl acetate to give the acylation product (VIII, R2a=C ~ , R3=H) (500 mg).
This was dissolved in formic acid (2.0 ml), stirred vigorously fox 60 min at room temperature and 12N HC1 (50~1) was added. The mixture was stirred at room temperature ~or 3 hr, diluted with water (2 ml) and toluene (20 ml) and evaporated at 30~C to dryness. The residue was triturated with isopropyl ether and the resulting precipitates were collected and washed with isopropyl ether. The solid was chromatographed on C-18 silica gel, eluting with 4:6 methanol-water to give the title compound as an amorphous solid, 80 mg (19%), M.p.
150 C (dec.). Est'd,purity 85% (based on HPLC).
IR : v max (HBr) in cm 1 3600-2600, 1765, 1660, 1620, 1530, 1350, 1025, 1010.
UV : ~max (MeOH) in nm (~) 236(17200), 256(14400).

, :-;

36f~

NMR: ~(D20 + NaHC03) in ppm 0.25-0.85 (4H, m), 1.20-1.60 (lH, m), 1.75 (3H, d, J=6 Hz), 3.45 and 3.75 (2H, ABq, J-18 Hz), 4.17 (2H, d, J=7 Hz), 5.40 (lH, d, J=5 Hz), 5.75-6.20 (3H, m), 7.14 (lH, s).

Gla~o, Japan Kokai 59-106492 (6/20/84) ~7~3~6~

Example 31 Diphenylmethvl 7-~2-(2-tritylaminothiazol-4-Yl)-2-tPro~arqYloxyiminoacetamido)l-3-((Z)-1-pro~enyl)-3-_ephem-4-carboxylate (VIII, R2a = CH2CHCH. R3 = H) To a cooled solution of 750 mg (1.65 m moles) of diphenylmethyl 7-amino-3-[( æ )-1-propenyl]-3-cephem-4-carboxylate hydrochloride (XIII, R3 = H) and 1.05 ml (5 m moles) of N,O-bis(trimethylsilyl)acetamide in 17 ml of dry methylene chloride was added a solution of 750 mg (1.65 m moles) of 2-tritylaminothiazol-4-yl-2-(2-propargyloxyimino)acetic acid (III, R2a = CH2C=CH) and 415 mg (2.0 m moles) o~ phosphorus pentachloride in 17 ml of dry methylene chloride, and the mixture was stirred for 1 hr at room temperature. The reaction mixture was poured into an aqueous NaHCO3 solution (30 ml) and diluted with 60 ml of ethyl acetate. The organic layer was washed with water (30 ml x 2) and brine (20 ml), dried over MgSO4 and concentrated under reduced pressure.
The oily residue was chromatographed on a column of silica gel (Wako gel-200, 20 g) which was eluted with CHC13. Fractions containing the desired product were combined and concentrated under reduced pressure to give 90.5 ~g ~97%) of the title compound. M.p. 155 C (dec).
IR vmax(KBr) in cm 1 3280, 2120, 1780, 1720, 1670.

US Patent 4,294,960 (10/13/81) Trademark ,, ~
, ~

3136~

, Example 32 7-LLz)-2-(2-Aminothiazol-4-~l)-2 t~ro~arqYloxyiminoacetamido)l-3-~(z)-l-pro~envll-3 ce~hem-4-carboxvlic acid tIa,R2 = CH2C-CH, R3 = H) A solution of 900 mg (1.18 m moles) of VIII
(R2a=CH2C-~H, R3=H) in 3 ml of 85% formic acid was stixred at room temperature for one hour. To the reaction mixture was added 0.3 ml of conc. HC1 and the suspension was ~tirred for 4 hr at ambient temperature.
The mixture was filtered and washed with a small portion of formic acid and concentrated under reduced pressure.
The residue was chromatographed on a column of reverse phase silica gel which was taken out of a PrepPAK-500/C18 cartridge column (Waters). The column was eluted with water and 30% MeOH-water, successively. Fractions containing the desired product were combined and lyophilized to afford 105 mg (22%) of the title compound.
IR : vmax (KBr) in cm 3400, 3280, 1770, 1670, 1630.
W : ~max (pH 7 phosphate buffer) in nm (~) 229 (17000), 285(14200).
NRM : ~(D2O ~ NaHCO3) in ppm 1.75 (3H, d, J=6 Hz, CH=CH-CH3), 3.61 (2H, ABq, 2-H), 4.98 (2H, s, O-CH2-C-CH), 5.39 (lH, ~, J=5 Hz, 6-H), 5.80 (lH, m, CH=CH-CH3), 5.92 (lH, d, J=5 Hz, 7-H), 6.03 (lH, d, J=11 Hz, CH=CHCH3), 7.22 (lH, s, thiazole-5H).

7~

Example 33 Di~hen~lmethvl 7-~(Z)-2-r2-tritvlaminot lazole-4-~1)-2-trityloxyimino-acetamido carbQxYlate (ViII ~a~= Tr R3 = H) To a mixture of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityl-oxyiminoacetic acid (III, R2a = Tr) (873 mg, 1.30 m moles) and dichloromethane (5 ml) was added phosphorus pentachloride (297 mg, 1.43 m moles) at -5 C. The mixture was allowed to stand for 20 min at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3-(1-propenyl)-3-cephem-4-carboxylate hydrochloride (XIII, R3 = H: 443 mg, 1 m mole) and N,0-bis(trimethylsilyl)acetamide (0.74 ml, 4.4 m moles) in dichloromethane (5 ml) at -5 C. The reaction mixture was allowed to stand for 20 min. at the same temperature and poured into ice-water. Extraction of the mixture with ethyl acetate and evaporation of the extracts under reduced pressure gave the crude product as an oil, which was chromatographed on a column of silica gel ( eluted with chloroform) to give the title compound ; as an amorphous powder. Yield 510 mg (48%).
IR : vmax (nujol) in cm 1 1780, 1720, 1680.

R. Bucourt et al., Tetrahedron 34, 2233 (1978) '~

8~

Exam~le 34 7-~(Z)-2-(2-Amlnothiazol-4-yl)-2-hydroxyiminoacetamidol-3-~(Z)-1-propenyll-~-cephem-4-carboxylic acid (Ia R2 =
~3 = ~ = H~
A mixture of VIII (R2a = Tr, R3 = H) (810 mg, 0.76 m mole) and 85 % formic acid (2 ml) was stirred for 1 hr at room temperature. To the reaction mixture was added hydrochloric acid (0.1 ml~. The mixture being stirred for 2 hr and evaporated under reduced pressure, the residue was triturated with isopropyl ether to give the crude product, which was chromatographed on a column of C-18 sil~ca gel (eluted with 20% aq. MeOH). The eluate wa~ aoncentrated under reduced pressure and freeze-dried to give the title compound as an amorphous powder. Yield 109 mg (35%). M. p. 170C (dec.). Est' a purity 75%.
Ir : vmax(KBr~ in cm 1 1770, 1760, 1630.
UV : ~max (pH 7 phosphate buffer) in nm (E11 %) 225(450), 282(370).
NMR : ~ (D2O ~ NaHCO3) in ppm 1.78 (3H, d, J=6Hz, CH=CH-CH3), 3.64 (2H, Abq, J=18Hz, 2-H), 5.40(1H, d, J=4Hz, 6-H), 5.70-6.25(3H, m, 7-H, vinyl-H), 7.14 (lH, d, thiazole-H).

...
.....

Exam~le 35 1-Acetoxvethvl_7-~tZ)-2-(2-aminthizol-4-yl)-2=
hydroxyiminoacetamidol-3-~(z~ ropenyll-3-cephem-4-carboxvlake (Ib R2-R3=H, R4=AX) To an ice-cooled and stirred solution of Ia (R2-R3=H, ~xample 34) (270 mg, 0.66 m mole) in dry DMF (2 ml) were added sodium carbonate (105 mg, 0.99 m mol) and a solution of 1-acetoxyethyl bromide (397 mg, 2.38 m mol) in DMF (0.6 ml) in three portions at 15-minute intervals.
The reaction was monitored by TLC (Merck Kieselgel 60 F254, 10:1 MeCN-H2O).I The mixture was stirred for additional 30 minutes, showing three major spots at Rf 0.11, 0.58 and 0.75. After dilution with ethyl acetate (50 ml), the resulting precipitate was filtered off, and the filtrate wa~hed with water (x 3) and subsequently with saturated aqueous sodium chloride, and dried over magnesium sulfate. The filtrate was evaporated to dryness ln vacuQ and the residue was dissolved in a small amount of chloroform. The solution was chromatographed on a Kieselgel 60 column (20 g), which ~a~ eluted with CHC13 and then with 1 : 20 mixture of MeOH and CHC13. Fractions showing a spot of Rf 0.58 by TLC were combined and concentrated to a small volume. To the concentrate was added isopropyl ether to give a precipitate, which was collected by ~iltration to afford 61 mg (19%) of the de`sired acetoxyethyl ester. M.p. 120-125 C.
Estimated purity 75% by HPLC.
IR : vmaX (KBr) in cm 1 1765, 1665, 1610, 1530, 1375.
UV : ~max (EtOH) in nm (E ) 223(19000), 264(12000), 285(12000).
NMR : ~(CDC13) in ppm 1.50 (3H, d, J=5.0 Hz, CHCH3), 1.65 (3H, d, J=6.0 Hz, =CHCH3), 2.07 (3H, s, COCH3), 3.45 (2H, br, SCH2), 5.08 (lH, d, J=5.5 Hz, 6-H), 5.5-6.0 (2H, m, 7-H & =CH), 6.15 (lH, d, J=10 Hz, 3-CH=), 6.96 (2H, m, thiazole-H & OCHCH3) ~., ,~ ~

- 76(a) -Packing: TSK gel 120 T (4x250 mm) Mobile phase: CH3CN/pH 6 phosphate buffer (2/3) 8~i~

Example 36 1-Acetoxyethyl 7-~(Z1-2-(2-Aminothiazol-4--Yl~-2-acetQxyiminoacetamidol-3-~(Z)-1-~Qro~enyll-3-ce~hem-~-carboxYlate (Ib, R2-Ac R3-H,_R4=AX) To a stirred mixture of Ia (R2=R3=H) (200 mg, 0.49 m mole) and K2CO~ (34 mg, 0.24 m mole) in dry DMF (5 ml) was added at 0 C a solution of 1-aaetoxyethyl bromide (81 m, 0.49 m mole) in dry DMF (0.1 ml). Potassium carbonate and the bromide were added to the mixture additional 4 times at 45-minute intervals. The reaction mixture was monitored by HPLC (Lichrosorb RP-18 4x300 mm, 4:1 MeCN-H2O). After the addition, the mixture was stirred for 30 min. The reaction mixture showing a major peak at 4.5 min (retentional time) was diluted with AcOEt ~40 ml), washed with water (x 3) and a saturated NaC1 solution, dried over MgSO4 and evaporated to a small volume. The concentrate was chromatographed on a Kieselgel 60 (8 g) column by eluting with a 1:20 mixture of MeOH-CHC13. The e~uate was monitored by HPLC and the fractions showing a peak of a retention time at 4.5 min were combined and conaentrated to ca. 2 ml. To the concentrate was added isopropyl ether (20 ml) to give 190 mg (72%) of the title compound as an isopropyl ether solvate. Est'd purity 85%.
IR : vmax(KBr) in cm 1 3280(w), 1770(s), 1680(m), 1540(m), 1215(s).
UV : ~max(MeOH) in nm (~) 231(17600), 293(9800).
NMR : ~(CDC13 + D2O) in ppm 1.5(3H, d, J=6 Hz, OCHCH3), 1.65 (3H, d-d, J=7 &1 Hz, =CHCH3), 2.05(3H, s, COCH3), 2.2 (3H, s, COCH3), 3.44 (2H, br, SCH2), 5.1 (lH, d, J=5 Hz, 6-H), 5.5-6.0 (lH, m, 3-CH-CH), 5.9(1H, d, J=5 Hz, 7-H), 6.15 (lH, d, J=11 Hz, 3-CH=CH), 6.89 (lH, m, OCHCH3), 6.92 (lH, s, thiazole-H).
Anal. Calcd. for,c2lH23Nso8s2 4/5[(CH3)2cH]2o C, 50.04; H, 5.57; N, 11.31; S, 10.35. Found : C, 49.78; H, 5.47; N, 10.90; S, 10.28.

Example 37 7-~(Z)-2-(2-Aminothiazol-4-yl)-2=(acetvloxy-iminoacetamido)l-3-~(Z)-1-~ropenyll-3-ce~hem-4-carbox~lic R ~HL
A suspension of 200 mg (1.30 m moles) of 1-hydroxy-lH-benzotriazole monohydrate, 631 mg (1.30 m moles) of 2-(2-tritylaminothiazol-4-yl)-2-acetoxyimino acetic acid and 268 mg (1.30 m moles) of dicyclohexylcar~odiimide was stirxed for 1 hr at 5 C. To the mixture was added 510 mg (1.26 m moles) of diphenylmethyl 7-amino-3-[(Z)-1-propenyl]-3-cephem-4-parboxylate. The mixture was stirred for S hr at room temperature and diluted with 50 ml of AcOEt. The reaction mixture was washed with lN HC1 (25 ml), water (25 ml) and brine (25 ml), dried over MgSO4, and concentrated under diminished pressure. The residue was chromatographed on a column of silica gel (30 g) which was eluted with toluene-AcOEt t10/1). Fractions showing a spot at Rf 0.20 ~y TLC (10:1 toluene-AcOEt) were combined and avaporated in vacuo. The residual oil (ca. 1.15 g) was di~solved in a mixture of 8 ml of 95%
TFA and 2 ml of anisole and the mixture was stirred for 1 hr in an ice-bath. The solution was concentrated under reduced pressure and triturated with isopropyl ether (40 ml) and n-hexane (10 ml) to give 432 mg of the crude product, which was purified by a column of Bondapak C-18, eluted with 30% aqueous MeOH. Fractions showing a peak of retention time 6.9 min. (HPLC) were combined, concentrated and lyophilized to give 153 mg (27%) of the title compound as an amorphous powder. M.p. 155C
(dec.). Estimated purity 65%. HPLC (Lichrosorb RP-18 4x300 mm, 3:7 MeOH-pH 7 buffer); retention time, 6.9 min.
IR : vmax (KPr) in cm 1 3260, 1775, 1765, 1665.
UV : ~max (EtOH) in nm (s) 230(20100), 292(12700).

;
:

~7~ ~ 8 NMR : ~(DMSO-d6l in ppm 1.63 (3H, dd, J=l & 7 Hz, =CHCH3), 2.16 (3H, s, OAc), 3.55 (br.s, 2H, 2-H), 5.22 tlH, d, J=5 Hz, 6-H), 5.70 (lH, m, =CHCH3), 5.76 (lH, dd, J=5 ~ 8 Hz, 7-H), 6.10 (lH, d, J=ll Hz, 3-CH=CH-), 7.05 (lH, s, thiazole-H), 7.28 (2H~ s, -NH2), 9.80 (lH, d, J=8 Hz).
Japan Kokai 59-184186 (10/19/84, Meiji Seika) 8~

Example 38 1-AcetoxyethYl 7-~tZ)-2-t2-aminothiazQl-4-yl)-2-acetQxyiminoacetamidol-3-~tZ)-1-~ropenvll-3-ce~hem-4-carboxylate tIb R2=AC R3=H. R4=AX) To a solution of 20 mg (0.05 m mole) of Ia (R2=AC, R3-H) in 0.2 ml of dry DMF was added 6 mg (0.05 m mole) of K2CO3 and the mixture was stirred for 5 minutes at 5C. 1-Acetoxyethyl bromide (10 ~1) was added to the mixture and the suspension was stirred for 1 hr at the same temperature. Th~e reaction mixture was diluted with 5 ml of AcOEt, washed successively with water (2 ml x 3) and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with 10 ml of isopropyl ether to give the desired acetoxyethyl ester, which was filtered off and dried. Yield 15 mg (63%). Spectral data of the product were consistent with those of the compound prepared in Bxample 36.

.....

3~

Example 39 Pivaloyloxyme~hyl 7-~(Z)-2-(2-aminothiazol-4-vl)-2-hydroxyiminoacetmidol-3-~(~)-1-pro~enyll-3-ce~h~m-4-carboxylate (Ib R2R3=H, R4=PV) To a stirred mixture of Ib (R2=R3=H) (200 mg, 0.49 m mole) and Na2CO3 (26 mg, 0.24 m mole) in dry dimethylacetamide (5 ml) was added at -5 C
pivaloyloxymeth~l iodide (118 mg, 0.49 m mole) and the mixture was stirred for 45 min. Sodium carbonate (13 mg, 0.12 m mole) and the iodide (59 mg, 0.12 m mole) were added again to the mixture and the mixture was stirred at the same temperature. After 30 min., the mixture showing spots at Rf 0.60 (major), 0.70 (minor) and 0.80 (minor) by TLC (merck Kieselgel 60 F254, 20:1 MeCN-H2O) was diluted with ethyl acetate (25 ml) and the solution was washed with water (x3) and a saturated NaC1 solution, dried over MgSO4 and evaporated to dryness. The residue was dissolved in a small amount of CHC13 and passed through a column of Kieselgel 60(13 g), which was washed with CHCl3 (50 ml) and eluted with 1:20 MeOH-CHCl3 (150 ml). The fractions showing a spot at Rf 0.60 by TLC were combined and evaporated. The residue was dissolved in benzene and the solution was lyophilized to afford 63 mg (25%) of the title compound. M.p. 101-104C. Estimated purity 80%. HPLC (Develosil 4x100 mm, 3:2 MeCN-pH 7 phosphate buffer): retention time, 4.6 min.
IR : vmaX (KBr) in cm 1 1780, 1755, 1570, 1530, 1120.
UV : ~max (MeOH~) in nm (~) 270(12000).
NMR : ~(CDC13 ~ D2O) in ppm 1.22 (9H, s, 3 x CH3), 1.56 (3H, dd, J=1 & 7 Hz, =CHCH3), 3.45 (2H, m, S-CH2) 5.11 (lH, d, J=4 Hz, 6-H), 5.5-5.95 (4H, m, 7-H, =CHCH3 &
OCH2O), 6.14 (lH, d, 3=11 Hz, 3-CH=), 7.02 (lH, s, thiazole-H).

8~3 -~2-Example 40 Acet~xymethyl 7-~tZ)-2-(2-aminothiazol-4-Yll-2-hYdroxyiminoacetamidol-3-~tZ)-1-~ronenyll-3-ce~hem-4-carboxylate fIb, R2 l ~
To a stirred suspension of Ia(R2=R3=H) ~280 mg, 0.68 m mole) and Na2CO3 (36 mg, 0.34 m mole) in dry DMF (5 ml) was added at -10-C over 10 min. a solution of acetoxymethyl bromide in dry DMF (104 mg, 0.68 m mole/100~1). After 30 min, additional Na2CO3 (18 mg, 0.17 m mole) and the bromide solution (52 mg, 0.34 m mole/50~1) were added in small portions over 10 min. The mixture was stirred at the same temperature for 30 min.
The reaction mixture showing four spots at Rf 0.10 (BMY-28232), 0.15, 0.60 and 0.75 by TLC (Merck Kieselgel 60 F254, 10:1 MeCN-H2O) was diluted with AcOEt (25 ml), washed with water (x3) and a saturated NaCl solution, dried over MgSO4 and evaporated. The residue was dissolved in a small amount of CHCl3 and charged on a column of Kiesel~el 60(18g), which was washed with CHCl3 (50 ml) and eluted with MeOH-CHCl3 (1 : 20, 250 ml). The fractions showing a spot at Rf 0.60 by TLC were combined and evaporated ln vacuo. The residue was dissolved in benzene and lyophilized to afford 45 mg (14%) of the title compound. M.p. 107-110 C. Estimated purity 70 %.
HPLC (lichrosorb 4x300 mm, 2:3 MeCN-H2O): retention time, 6.0 min.
IR : vmaX (KBr) in cm 1 1770, 1665, 1530, 1370, 1200, 1000, 985.
UV : ~max (MeOH) in nm (~) 268(10900).
NMR : ~(CDC13 +'D2O) in ppm 1.65 (3H, s, J=7 Hz, =CHCH3), 2.1 (3H, s, COCH3), 3.43 (2H, br, SCH2), 5.1 (lH, d, J=5 Hz, 6-H), 5.3-5.95 (4H, m, 7-H, =CHCH3 &
OCH2O), 6.15 (lH, d, J=11 Hz, 3-CH=), 6.96 (lH, s, thiazole-H).

AM=-CH2OCOCH3 ~ , .

~ ~''3~

Example 41 carboxylate hydrQc_loride ~XIII (E~ R3=CH3 R4a=CHP
A mixture of diphenylmethyl 7-amino-3-[(Z)-1-butenyl]-3-cephem-4-carboxylate hydrochloride (from Example 6) (2.9 g, 6.5 m moles) and benzophenone (1.2 g, 6.5 m moles) in methanol (300 ml) was irradiated with a low pressure Hg lamp (2537 A, 6W) at room temperature for 26 hr. The solvent was evaporated in vacuo and the residue was dissolved in chloroform. The solution was treated with carbon and filtered. The filtrate was diluted with ether to precipitate 2.2 g (76%) of the title compound E isomer contaminated with 10% of the Z
isomer which was used for the next step without further purification.
IR : v max (KBr) in cm 1 1780, 1720, 1625.
UV : ~ max (MeOH) in nm (s) 298(10200).
NMR : ~ (DMSO-d6) in ppm 0.97 (3H, t, J=7 Hz, CH3), 2.15 (2H, m, CH2CH3), 3.84 (2H, br-s, 2-H), 5.15 (lH, d, J=5 Hz, 6-H), 5.30 (lH, d, J=5 Hz, 7-H), 6.65 (lH, d, J=16 Hz, 3-CH=), 6.97 (lH, s, OCH), 7.45 (lOH, s, phenyl-H).
HPLC : Lichrosorb RP-18 (4x250 mm), 3:2 CH3CN-pH
7 phosphate buffer, 2 ml/min. Retention time: Z isomer, ~; 5.1 min ; E isomer, 6.7 min.

l~ ,' ..

7~38~

~ E~e 42 Di~henyl~eth~l 7-~t~L~L2-aminQ~hiazol-4-yl)-2-methoxyiminoacetamidol-3-~(E)-1-~utenYll-3-cePhem-4-carboxYlate (XIV (EL~ R2=R3=CH3, R4a-CHPh2l A suspension of crude diphenylmethyl 7-amino-3-[(E)-l-butenyl]-3-cephem-4-carboxylate hydrochloride (1.97 g, 4.3 m moles) in AcOEt (30 ml) was shaken with aqueous NaHCO3 to give a clear two-layer solution. The organic layer was separated, washed with water and than an aqueous saturated NaCl solution, dried over MgSO~ and concentrated ln YaCUO. The residue was dissolved in DMF
(20 ml). To the solution was added 1-[(Z)-2-~2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzotriazole (2.07 g, 6.5 m moles). The mixture was stirred at room temperature for 1 hr and diluted with AcOEt (100 ml).
The diluted solution was washed with aqueous NaHCO3, water and aqueous NaCl, successively, dried over MgSO4 and evaporated in vacuo. The residue was chromatographed on a silica gel column (50 g) and eluted with 2:1 toluene-ethyl acetate to yield 1.58 g (61%) of the title compound.
IR : v max (KBr) in cm 1 1770, 1720, 1670.
UV : ~max (MeOH) in nm (s) 297(18800).
NMR : ~ (CDC13 ~ D2O) in ppm 0.97 (3H, t, J=7 Hz, CH2CH3), 2.12 t2H, m, CH2CH3}, 3.52 (2H, s, 2-H), 4.00 (3H, s, OCH3), 5.10 (lH, d, J=4.5 Hz, 6-H), 5.93 (lH, d, J=4.5 Hz, 7-H), 5.7-6.3 (lH, m, =CH-CH2), 6.74 (lH, s, thiazole-H), 6.96 (lH, s, O~H), 7.25 ~lOH, s, phenyl-H).

~ 7~

Exam~le 43 7-~(z)-2-(2-Amino~hiazol-4-yl)-2-methoxyiminoacetamid 3-~(E)-1-bu~envll-3-c~ em-4-carboxylic acid (Ia (E), R2=R3-CH3l A mixture of diphenylmethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-1-butenyl]-3-cephem-4-carboxylate (650 mg, 1.1 m moles), TFA t3 ml~ and anisole (1 ml) was stirred at 5 C for 30 min and diluted with isopropyl ether. The resulting precipitate was collected by filtration. It was dissolved in formic acid (3 ml) and chromatographed on a column of the packing (100 ml) of a PrepPAK cartridge (Waters), which was washed with water and then eluted with 30% methanol. rrhe eluate was monitored by HPLC and the desired fractions were combined, concentrated and lyophilized to give 277 mg (59%) of the title compound .
M.p.>170'C (grad. dec.). Estimated purity 90%.
IR : v max (KBr) in cm 1 1770, 1660.
UV : A max (pH 7 phosphate buffer) in nm (~) 232(15700), 292(22400).
NMR : ~ (D2O ~ NaHCO3) in ppm 1.18 (3H, t, J=7 Hz, CH2CH3), 2.30 (2H, m, CH2CH3), 3.83 (2H, s, 2-H), 4.15 (3H, s, OCH3), 5.37 (lH, d, J=5 Hz, 6-H), 5.92 (lH, d, J=5 Hz, 7-H), 5.9-6.4 (lH, m, =CHCH2), 5.66 (lH, d, J=16 Hz, 3-CH=), 7.18 (lH, s, thiazole-H).
Anal. Calcd. for C17H1gN5O5S2 1/2H2 C, 4.51 ; N, 15 69 ; S, 14.36. Found: C, 45.63 ; H, 4.28 ;
N, 15.33 ; S, 14.27.

The 3-trans-butenyl cephalosporin Ia (E, R2=R3=CH3), which was identical with that described in Example 15.

~, ~

~,7g~

Exam~le 44 ' ~c~e~*3~e-D~ (z)=2-(2-aminQ~hiazol-4-yl~-2-methoxyiminoacetamido~l-3-~tE~-2-butenvll--3-cephem-4-carbox-~ate (Ib LE) R2=R3=CH3, R4-AX
A mixture of Ia (E) (R2=R3=CH3) ~438 mg, 1 m mole) a~d K2CO3 (207 mg, 1 5 m moles) in D~F (10 ml) was treated with 1-acetoxyethyl bromide (250 mg, 1.5 m moles) by a similar procedure to that described in Example 16 to give 350 mg (67%) of the desired AX ester, which was identical with that in Example 16. M.p. 110-115 C.
Estimated purity, 90% by HPLC.
IR : vmaX (KBr) in cm 1 1760 (br.), 1670, 1610.
UV : ~max (MeOH) in nm () 232(16600), 2g8 ( 1 9300 ) .
NMR : ~ (CDCl3) in ppm 1.05 (3H, t, J=7 Hz, CH2CH3), 1.54 (3H, d, J=6 Hz, CHCH3), 2.08 (3H, s, COCH3), 2.0-2.4 (2H, m, -CH2CH3), 3.57 (2H, s, 2-H), 4.05 (3H, s, OCH3), 5.07 (lH, d, J=5 Hz, 6--H), 5.8-6.3 (2H, m, 7-H & -CHCH2 ), 6.86 (lH, s, thiazole-H), 6.8-7.1 (2H, m, OCH & 3-CH=) Anal. Calcd. for C21H2sNsO7S2 1/4l(cH3)2cH]2o C~
49.21, H, 5.23 ; N, 12.75 ; S, 11.68. Found : C, 49.44 ;
H, 5.28 ; N, 12.24 ; S, 11.70.

, ~

8~3 Example 45 7-Amino-3-~E)~ ropenvl1-3-cephem-4-carboxylic acid (XIII (E) R3 ~
A solution of 7-amino-3-[(Z)-1-propenyl]-3-cephem-4-carboxylic acid (1.2 g, 5 m moles) an~ benzophenone (900 mg, 5 m moles) in methanol (800 ml) containing 1 ml of 6N
hydrochloric acid waslirradiated with low-pressure Hg lamp (2537 A, 6W) at room temperature for 44 hrs. The reaction mixture was evaporated to dryness and the residue was ~istributed in a mixture of 0.15N HC1 (200 m].) and ether (200 ml). The aqueous layer was separated, treated with active carbon and filtered. The filtrate was adjusted to pH 3 with a dilute NaOH solution and cooled to give a precipitate. It was collected by filtratlon and washed with water and acetone to give 476 mg of the title compound E isomer, melting at 245 C
(grad. dec.). The second crop (195 mg) was obtained by concentrating the filtrate to 30 ml. Total yield 671 mg (56%). The product contained less than 5% of the corresponding Z isomer.
IR : v max (K~r) in cm 1 1800, 1620, 1540, 1420, 1360.
UV : ~ max (pH 7 phosphate buffer) in nm () 292(15000).
NMR : ~ (D2O + Na2CO3) in ppm 1.78 (3H, d, J=6 Hz, =CH-CX3), 3.62 (2H, s, 2-H), 5.03 (lH, d, J=4.5 Hz, 6-H), 5.3-6.2 (2H, m, =CH & 7-H), 6.52 (lH, d, J=16 Hz, 3-CH=C).
Anal. calcd. for C10Hl2N2o3s-l/2H2o: C, 48.18 ; H, 5.25 ; N, 11.24 ; S, 12.86. Found: C, 47.88 ; H, 4.83 ;
N, 10.79 ; S, 12.83.

A 4:1 mixture of Z and E isomers.

8~

Example 46 7-~(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamidol-3-~(E)-1-pro~enyll-3-cephem-4-carbQxvlic acid (Ia (E), ~ 3~_B~=~
To a stirred solution of 7-amino-3-trans-propenyl derivatives XIII (E, R3=R4a=H) (720 mg, 3 m moles) and sodium bicarbonate (504 mg, 6 m mole~) in 50% DMF (60 ml) was added 1-~(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzotriazole (954 mg, 3 m moles) andthe mixture was stirred for 30 min. An additional amount of the active ester (1.81 g, 6 m mo:Les) was added in four portions at 30-min intervals. The mixture was stirred for additional 2 hr at room temperature and passed through a column packed with the packing of prepPAK-C18 cartridge (300 ml, Waters). The column was washed with water and then eluted successively with 10% methanol and 20% methanol. Fractions of 20% methanol eluate showing a peak at retention time 5.57 min by HPLC were collected and evaporated to dryness. The residue was dissolved in methanol and filtered. The filtrate was concentrated to 5 ml and the residue was triturated with a mixture of ether-isopropyl ether to give 805 mg (63%) of the title compound, melting at 180-C (grad. dec.), 80% pure by 25HPLC .
IR : v max (KBr) in cm 1770, 1670, 1630, 1540, 1380, 1040.
UV ~ max (MeOH) in nm (E) 234(1700o)~
293(20000).
30NMR : ~ (D2O ~ Na2CO3) in ppm 1.93 (3H, d-d, J=6 &
1.5 Hz, =CH-CL3), 3.76(2H, 9, 2-H), 4.12(3H, s, OCH3), 5.32(1H, d, J=4.5 Hz, 6-H), 5.86(1H, d, J=4.5 Hz, 7-H), 5.8-6.3 (lH, m, =CH-CH3), 6.61(1H, d-d, J=16 & 1.5 Hz, , CH=C), 7.13(1H, s, thiazole-H).
Anal. Calcd. for C16H17N5O5S2 : C, 45.38 ; H, 4.05 ;
N, 16.54 ; S, 15.14. Found : C, 45.57, 45.41 ; H, 4.37, 4.29 ; N, 15.94, 15.76 ; S, 13.90, 13.62.

~'~ . ^l 86~3 - 88 (a) *Packin~: Lichrosorb RP-18 (4 x 300 nm), Mobile Phase:
MeOH-pH 7 buffer (35: 65) Exam~le 47 1 -AcetoxYethyl 7- ~ ( Z ) r2- ( 2-aminothiazol-4-Yl)-2-methoxyiminoacetamidol-3-~(E~-1-propenvll-3-cephem-4-carboxvlate (Ib (E), R2=CH3 R3-H R4=AX
To a stirred mixture of 317 mg (0.75 m mole) of the trans-propenyl cephalosporin Ia(E, R2=CH3, R3=H} and 104 mg (0.75 m mole) of potassium carbonate in 5 ml of DMF
was added at 0-5C a solution of 167 mg (1 m mole) of 1-acetoxyethyl bromide in 0.5 ml of DMF and the mixture was stirred at 5 C for 15 min. An additional amount of each of potassium carbonate (204 mg, l.S m moles) and the bromide solut.ion in DMF (334 mg, 2 m moles/1 ml) was added in two portions over a period of 15 min to complete the reaction. The mixture was stirred at 5 C for additional 30 min and diluted with 150 ml of ethyl acetats. The dilute ~olution was washed with water and aqueous NaCl, dried w~th MgSO4, and concentrated to dryness. The oily residue was dissolved in a small volume of CHC13 and chromatographed on a silica gsl column (Merck Kieselgel 60, 40 g), which was washed with chloroform and eluted with chloroform-methanol (50:1).
The desired fractions showing a spot at Rf 0.40 by ~LC
(silica gel, chloroform-methanol, 10:1) and a peak at retention time 7.7 min by HPLC (acetonitrile-pH 7 buffer, 1:1), were collected and evaporated to dryness to give an oily residue, which was triturated with a mixture of ether and isopropyl ether to give 270 mg (70.5 %3 of the desired title ester, melting at 140~C (dec.). Estimated purity 80% by HPLC.
IR : v ~ax (KBr) in cm 1 1770, 1670, 1620, 1540, 1380, 1210, 1100, 1070, 1040.
UV : ~ max (Me~H) in nm (f) 234(17000), 297(19000).
NMR : ~ (CDCl3) in ppm 1.53 (3H, d, J=5 Hz, C-CH3), 1.86 (3H, d, J=6 Hz, CH=CH-CH3), 2.08 (3H, s, OCOCH3), 3.55 (2H, br-s, 2-H), 4.05 (3H, s, OCH3), 5.07 (lH, d, J=4.5 Hz, 6-H), 5.38 (2H, br-s, NH2), 5.95 8~f~
- 89(a) -(lH, d, J=4.5 Hz, 7-H~, 5.7-6.2 (lH, m, CH=CH-CH3), 6.81 :~ (lH, s, thiazole-H), 6.9-7.1 (2H, m, CH-CH3 & CH=CH-CH3), 7.55 (lH, d, J-8 Hz, NH).

- 9o -Example 4~
Dipheny methyl 7-~(Z)-2-(2-tritYlamin~thiazol-4-yl~ 2-methoxyimi_oacç~amidol-3-~(tri~henvlphos~h~r-anylidene)methyll-3-cePhem-4-carboxylate (VII, R2a=CH
A solution of diphenylmethyl 7-~(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(triphenylphosphonio)methyl]-3-cephem-4-carbo~ylate iodide (3.0 g, 2.5 m moles) in dichloromethane (40 ml) was shaken with lN NaOH (10 ml) until the spot of the starting material disappeared on TLC (silica gel, CHCl3-MeOH=10:1). Organic layer was separated and concentrated under reduced pressure. The residue was triturated with n-hexane and the prod\uct was collected by filtration to give 2.5 g (93%) of the title compound.
IR : v max (KBr) in cm 1 1760, 1740, 1560.
UV : ~ max (CH2Cl2) in nm (~) 310(8800), 388(15000).

) US 4,486,586, Column 33, Preparation No. 17, Compound VIII-1.

386~
Example 49 Diphenvlmethyl 7-~(Z)-2-(2-tritvlaminothiazol-4-Yl)-2-methoxyiminoacetamidol-3-~3-(Z)-acetoxv-1-pro~enYll-3-cephem-4-carboxylate (VIII, R2a=CH3, R3=oAc) A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(triphenylphosphoranylidene)methyl-3-cephem-4-carboxylate (2.13 g, 2.9 m moles) and acetoxyacetaldehyde1) (0.61 g, 6.0 m moles) in dichloromethane (10 ml) was stirred f~r 3 hr at room temperature. The mixtures was concentrated under reduced pressure and the residue was chromatographed on a column of silica gel. The column was eluted with n-hexane-CHC13 (1:2) and the fractions containing the desired product were combined.
Evaporation of the solvent under reduced pressure afforded 1.0 g (56%) of the title compound.
IR : ~ max (liq.) in cm 1 1785, 1735, 1675, 1430, 1230, 1180.
NMR : ~(CCl4) in ppm 6.08 (lH, d, J=13 Hz).

1) J. Corbet and C. Benezra, J. Org. Chem, 46, 1141 (1981).

t Exam~le 50 DlphenylmethYl_7-amino-3=~(Z~-3-acetoxy-1-~ropenyll-3-cephem-4-carbQx~vlate (XIII R3=oAc) ~o a cooled mixture of LiBr (8.6 g, 0.1 mole) in dry DMF (40 ml) were successively added a solution of diphenylmethyl 7-benzylideneamino-3-~(triphenylphosphranylidene)methyl]-3-cephem-4-carboxylate (XI) (7.3 g, 10 m moles) in dry methylene chloride (200 ml) and acetoxyacetaldehyde (3.06 g, 0.03 mole), and the mixture was stirred at room temperature for 44 hrs. After concentration to 50 ml, the oily residue was diluted with ethyl acetate and the solution was washed with water~, a saturated NaCl solution, dried over MgSO4 and concentrated to 100 ml. To the stirred concentrate was added a solution of the Girard T reagent (5g, 0.03 mole) in methanol (100 ml) containing 1 ml of acetic acid and the mixture was stirred at room temperature for 40 min. After evaporation of the solvent, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with sodium hicarbonate solution, water, a saturated NaCl solution and dried with MgSO4. Evaporation of the solvent gave an oily residue which was chromatographed on a silica gel column (Merck Kiesel gel 60, 100 g) by eluting with chloroform. The eluate was monitored by TLC
(chloroform:methanol=30:1) and the fractions showing a spot at Rf 0.30 were combined and concentrated to afford an oily residue, whi ch was triturated with ether-isopropyl ether ~o give 2.8 g (60%) of the title compound, melting at 130-135-C (dec.) IR : ~ max (KBr) in cm 1 1770, 1720, 1390, 1370, 1220, 1100.
UV : ~max (MeOH) in nm (s) 286(7500).
NMR : ~ (CDCl3) in ppm 1.83 (2H, br s, NH2), 2.02 (3H, s, COCH3), 3.27 (lH, d, J=18 Hz, 2-H), 3.65 (lH, d, J=18 Hz, 2-H), 3.9-4.9 (2H, m, CH2OAc), 4.78 (lH, d, J=4.5 Hz, 6-H), 5.02 (lH, r ~ ''~
.:

38g~3 d, J=4.5Hz, 7-H), 5.3-5.8 (lH, m, =CH-CH2-), 6.27 (lH, d, J=ll Hz, CH=CH-CH2), 6.97 (lH, s, CH-Ph), 7.2-7.6 (lOH, m, phenyl H).
Anal. Calcd. for C25H24N205S C, 6 6.03; S, 6.90.
Found: C, 64.79; H, 5.33; N, 5.89; S, 6.94.

~ ~r~98t~3 ~94-Example 51 Diphenylmethyl 7-~(Z)-2-(2-aminothiazol-4-Yl)-2-methoxyiminoacetamidol-3-~(Z)-3-acetoxy-1-ProPenYll-3-ce~hem-4-carbQxvlate tXIV, R3=oAc) A mixture of diphenylmethyl 7-amino-3-[(Z)-3-acekoxy-1-propenyll--3-cephem-4-carboxylate (2.32 g, 5 m moles) and benzotriazol-l-yl (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (1.9 g, 6 m moles) in 100 ml of dry THF was stirred at room temperature for 20 hr and the solvent was evaporated to dryness. After extraction with ethyl acetate (200 ml), the solution was washed with aqueous sodium bicarbonate, a saturated NaCl solution and water, dried with MgSO4 and concentrated to give an oily residue, which was chromatographed on a silica gel column (Kiesel gel 60, 80 g Merck), by eluting successively with chloroform and chloroform-methanol (50:1). The desired fractions eluted with chloroform-methanol (50:1), were combined and concentrated to give a residue which was triturated with ether-isopropyl ether to give 1.97 g (61%) of the title compound, melting at 120C (grad.
dec.).
IR :` vmaX (KBr) in cm 1 1780, 1730, 1670, 1610, 1530, 1370, 1220, 1030.
UV : ~max (MeOH) in nm (E ) 286(14000).
NMR : ~ ~CDCl3) in ppm 1.97 (3H, s, COCH3), 3.42 (2H, s,2-H), 4.02 (3H, s, OCH3), 5.15 (lH, d, J=4.5 Hz, 6-H), 6.03(1H, d-d, J=4.5 & 9 Hz, 7-H), 6.27 (lH, d, J=11 Hz, CH=CH-CH2), 6.78 (lH, s, thiazole-H), 6.94(1H, s, CHPh), 7.2--7.6 (lOH, m, phenyl-H), 8.03 (lH, d, J=9 Hz, NH).

`i' `'-~

Exam~le 52 7-LLZ)-2-(AminQthiazol-4-yl)-2-meth~xyiminoacetamidol-3 ~(Z)-3-acetoxy-1-~rQ~nyll-3-ce~hem-4-carbQxYlic acid (Ia. R2=CH3 R3=oAc A) From XIV (R3=oAc) - A mixture o~
diphenylmethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-3-acetoxy-1-propen~1]-3-cephem-4-carboxylate (1.88 g, 2.9 m moles), 3 ml of anisole and 9 ml of TFA was stirred at room temperature for 10 min and the mixture was concentrated to 5 ml.
After dilution with 50 ml of ether and 100 ml of isopropyl ether, the resulting precipitate was collected by filtration to give 1.5 g of crude trifluoroacetate of Ia (R2=CH3, R3-oAc). It was chromatographed on a column packed with the packing of prepPAK-C18 cartridge ~400 ml, Waters), whiah was successively eluted with water and 20 methanol. The desired fractions eluted with 20%
methanol were collected and concentrated to give solid, which was dlssolved in 100 ml of methanol and the solution was treated with active carbon and concentrated to 10 ml. To the chilled concentrate was added ether (200 ml) and the resulting precipitate was collected by filtration, washed with ether and dried ln vacuo over P2O5 to give 938 mg (67%) of the title compound, melting at 160-C (grad. dec.).
IR : vmax (KBr) in cm 1 1770, 1720, 1670, 1620, 1530, 1370, 1230, 1030.
U~ : ~max (pH 7 phosphate buffer) in nm (E ) 231(17000), 284(16000).
NMR : ~(D2O + Na2CO3) in ppm 2.22 (3H, s, COCH3), 3.47 (lH, d, J=18 Hz, 2-H), 3.76 (lH, d, J=18 Hz, 2-H), 4.13 (3H, s, OCH3), 5.39 (lH, d, J=4.5 Hz, 6-H), 5.92 (lH, d, J=4.5 Hz, 7-H), 6.36 (lH, d, J=11 Hz, CH=CH-CH2), 7.14 (lH, s, thiazolelH).
Anal. Calcd. for C18H19N5O7S2 1/2H20 C, 4-4.11 ; N, 14.28 ; S, 13.07. Found: C, 44.29 ; H, 4.07 ;
N, 13.98; S, 13.03.

, --96-B) From VIII (R2a=CH3, R3=oAc) - Diphenylmethyl 7-[(Z)-2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido-3-[(Z)-3-acetoxy-1-propenyl]methyl-3-4-carboxylate (1.0 g, 1.12 m moles) was dissolved in 85% formic acid (5 ml) and the solution was stirred for 2 hr at room temperature. ~ydrochloria acid (0.1 ml) was added and the stirring was continued for further 2 hr.
After removal of excess formic acid by evaporation, the mixture was triturated with isopropyl ether to precipitate the crude product, which was collected by filtration and purified by chromatography to give 154 mg (31%) of the title compound, which was identical with that obtained from the procedure A.

-Exam~le 53 1-AcetoxyethyL 7-~(Z)-2-l2-aminothiazol-4-Yl)-2-methox~iminoace~amidol-3-~(Z)-3-acetox~ ro~enYll-3-ce~hem-4-carbQ_~late ,(Ib. ~=~
To a cooled and stirred solution of Ia (R2=CH3, R3=oAc) (362 mg, 0.75 m mole) in DMF (5 ml) were added K2CO3 (312 mg, 2.25 m moles) and a solution of 1-acetoxyethyl bromide (501 mg, 3 m moles) in DMF (1.5 ml) in three portions at 15 minute intervals, and the mixture was 8 tirred for additional 30 minutes. After dilution with ethyl acetate (200 ml), the solution was washed with water, a saturated NaCl solution, dried and evaporated to dryness. The oily residue was purified by chromatography on a silica gel column (Merck Kiesel gel 60, 40 g) by eluting successively with chloroform and chloroform-methanol ~50:1). The fractions showing a peak at retention time 6.1 min by HPLC were collected and evaporated to dryness to give a residue which was triturated with ether~to give 236 mg (68%) of the title aompound. Estimated purity 60%. This compound contained ca. 25% of ~2 isomer as an impurity. M.p. 110-C (grad.
dec.).
IR : vmaX (KBr) in cm 1780, 1760, 1740, 1670, 1610, 1530, 1370, 1230, 1070, 1030.
UV : ~ max (MeOH) in nm (~) 268(15000).
NMR : ~ (CDC13) in ppm 1.51 (3H, d, J=6 Hz, CH-CL3), 2.04 (3H, s, COCH3, 2.08 (3H, s, COCH3), 3.03 and 3.60 (1. 5H, ABq, J=18 Hz, 2-H), 4. 05 (3H, s, OCH3), 6.17 (0.3H, s, ~2-H), 6.26 (lH, d, J=11 Hz, CH=CH-CH2).

HPLC (Lichrosorb RP-18, 4x300 mm, 50~ acetonitrile-buffer (pH 7).

, ,, ~, -9~-Exam~le 54 Diphenylmethyl 7-amino-3-~(E)-3-acetoxY-1-pro~enYll-3-cephem-4-carboxylate tXIII_(E) R3=H R4a=CHPh21 To a solution of diphenylmethyl 7-amino-3-[~Z)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate (2.7 g, 5.8 m moles) and acetophenone (720 mg, 6 m moles) in methanol (lL) was added lN hydrochloric acid ~6 ml) The solution was irradiated with low-pressure Hg lamp (2537 A, 6W) 10 under stirring at room temperature for 22 hrs and evaporated to dryness. The residue was dissolved in ethyl acetate (300 ml~) and the solution was washed with aqueous sodium bicarbonate, water, a saturated NaCl solution and dried with MgSO4. After evaporation of the 15 solvent, the residue was chromatographed on a silica gel column (Merck Kiesel gel 60, 100 g) by eluting with chloroform. The fractions showing a spot at Rf 0.45 by TLC (chloroform:methanol = 30:1) were combined and concentrated to give a residue. Trituration of the 20 residue with ether gave 910 mg (34%) of the title compound, melting at 157C (dec.) The latter fraction showing a spot at 0.40 on TLC
gave 583 mg (22%) of the starting Z isomer.
IR : vmaX (KBr) in cm 1 1760, 1730, 1710, 1360, 25 1240, 1210, 1090.
UV : ~max (MeOH) in nm () 301(15000).
NMR : ~ (CDC1'3) in ppm 1.8 (2H, br.s, NH2), 2.02 (3H, s, COCH3), 3.56 (2H, s, 2-H), 4.73 (lH, d, J=4.5 H2, 6-H), 4.95 (lH, d, J=4.5 Hz, 7-H), 6.87 (lH, d, J=16 Hz, 30 CH=CH-CH2), 7.05 (lH, s, CHPh), 7.3-7.6 (lOH, m, Ph).
Anal. Calcd- for C25H24N2O5S C, 64-N, 6.03 ; S, 6.72. Found : C, 64.28 ; H, 5.21 ; N, 5.88 ; S, 6.82.

Example 55 Di~hen~l~ethyl 7-~(Z)-2-l2-aminothiazol-~yl)-2-methoxviminoacetamidol-3-L(E)-3-acetoxy-1-~ro~enYll-3-ce~hem-4-carbQxvlate (XIV (E) R2=CH
CHPh2L
A mixture of Diphenylmethyl 7-amino-3-[(E)-3-- acetoxy-1-propenyl]-3-cephem-4-carboxylate (930 mg, 2 m moles) and 1-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzotriazole (954 mg, 3 m moles) in dry TH~ (40 ml) was stirred at room temperature for 4 hrs and the mixture was concentrated to dryness. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with an a~ueous sodium bicarbonate, water, a saturated NaCl solution and dried with MgSO4.
- After evaporation of the solvent, the residue was chromatographed on a silica gel column (Merok Kiesel gel 60, 40 g) by eluting successively with chloroform and chloroform-methanol (50%). The desired fractions were collected and evaporated to dryness and the residue was triturated with ether to give 910 mg (70%) of the title compound, melting at 110-C (grad. dec.).
IR : v max (KBr) in cm 1780, 1730, 1680, 1610, 1530, 1380, 1220.
UV : ~ max (MeOH) in nm (~) 297(22000).
NMR : ~ (CDC13) in ppm 1.99 (3H, s, COCH3), 3.56 (2H, s, 2-H), 4.04 (3H, s, OCH3), 4.52 (2H, d, J=6 Hz, CH=CH--CH2), 5.08 (lH, d, J=4.5 Hz, 6-H), 5.97 (lH, d-d, J=8 & 4.5 Hz, 7-H), 5.7-6.2 (lH, m, CH=CH-CH2), 6.83 (lH, s, thiazole-H), 6.96 (lH, s, CHPh).

~7~

Example 56 7-~tZ)-2-r2-Aminothiazol-4-Yl)-2-methoxyiminoacetamidQ
3-~tE)-3-acetoxy-1-propenyll-3-cephem-4-carbQx~lic acid tIa lE), ~-CH3 ~
A mixture of diphenylmethyl 7-[(Z)-2-~2--aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-3-acetoxy-1-propenyl)-3-cephem-4-carboxylate (870 mg, 1.34 m moles) and anisole (0.8 ml) was dissolved in 2.4 ml of trifluoracetic acid and the solution was stirred at room temperature for 15 min. The rea~tion mixture was worked up and purified by a similar procedure to that described in Example 52 (procedure A) to g.ive 429 mg (66%) of the title compound, melting at 180-C (grad. dec.).
IR : v max (~KBr) in cm 1 1770, 1730, 1670, 1630, 1530, 1370, 1240, 1030.
UV : ~max (pH 7 phosphate buffer) in nm () 231(17000), 292~26000).
NMR : ~(D2O + Na2CO3) in ppm 2.20 (3H, s, COCH3), 3.75 (2H, s, 2-H), 4.10 (3H, s, OCH3), 4.75 (2H, s, CH2OAc), 5.32 (lH, d, J=4.5 Hz, 6-H), 5.88 (lH, d, J=4.5 Hz, 7-H), 5.9-6.3 (lH, m, CH~CH-CH2), 6. 73 (lH, d, J=l6 Hz, CH-CH-CH2), 7.09 (lH, s, thiazole-H).

, .~
, .. . .

, . . .

- Exam~le 57 1-Acetoxyethvl 7-llZ)-2-12-aminothiazol-4-vl~-2-methoxyiminoacetamidol-3-~(E)~3-acetoxy-1-~oPenyll-3-cephem-4-carboxylate (Ib (E~ R2=CH3 R3=oAc R4=AX) To a stlrred solution of Ia (E) (R2=CH3, R3-oAc) (241 mg, 0.5 m mole) in dry DMF (4 ml) were added at 0-5 C K2CO3 (140 mg, 1 m mole) and a solution of 1-acetoxyethyl bromide (336 mg, 2 m moles) in DMF (2ml) in four portions at 15-minute intervals, and the mixture was stirred at the same temperature for additional 1 hr.
After dilution with ethyl acetate, the solution was washed with water and a saturated NaCl solution, dried with MgSO4 and concentrated to dryness. The residue was chromatographed on a silica gel column (Merck Kiesel gel 60, 30 g) by eluting with chloroform and chloroform-methanol (50:1), successively. The desired fractions eluted with chloroform-methanol were collected and evaporated to dryness~and the residue was triturated with ether to give 185 mg (65%) of the title aompound, melting at 120~C (grad. dec.).
IR : vmaX (K~r) in cm~1 1770, 1680, 1620, 1500, 1390, 1240, 1080, 1040.
UV : ~max (MeOH~ in nm (s) 232(18000), ~95(21000).
NMR : ~ (CDCl3) in ppm 1.56 (3H, d, J=6 Hz, CH-CH3), 2.08 (6H, s, COCH3), 3.6 (2H, br-s, 2-H), 4.06 (3H, s, OCH3), 5.07 (lH, d, J=4.5 Hz, 6-H), 5.39 (2H, br-s, NH2), 5.7-6.4 (2H, m, CH=CHCH2 & 7-H), 6.81 (lH, s, thiazole-H), 7.56 (lH, d, J=8 Hz, NH).

38~3 Example 58 Diphenylmethvl 7-~(Z)-2-(2-tritylaminothiazol-4-vl)-2-trityloxviminoacetamidol-3-chloromethvl-3-cephem-4-carboxvlate (IV, R2a=Tr To a mixture of (Z)-2-(2-tritylaminothiazol-4-yl)-2-trithyloxyiminoacetic acid ) (6.71 g, 10 m moles) and 1-hydroxybenzotriazole mono hydrate (1.53 y, 11 m moles) in THF (50 ml) was added dicyclohexylcarbodiimide (2.06 g, 10 m moles) at 5C and the mixture was stirred for 2 hr at the same temperature and filtered to give a solution of active ester. A suspension of diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (4.51 g, 10 m moles) in ethyl acetate (50 ml) was washed with saturated NaHCO3 solution (10 ml x3), water and dried.
The solution was poured into the solution of active ester prepared above with stirring at O C and the mixture was allowed to stand for 2 days at 5 C. After evaporation, the residue was chromàtographed on a column of silica ge1 (silica gel 60, 100 g~ and the column was eluted with CHCl3-n-hexane (2:1). The ~ractions containin~ desired product was concentrated under reduced pressure.
Trituration of the residue with n-hexane gave 10.0 g (94%) of the title compound as an amorphous powder.
IR : vmaX (KBr) in cm 1 1780, 1720, 1680, 1490.
UV : ~max (CH2C12) in nm (~) 245(23000).
NMR : ~ (CDCl3) in ppm 3.4 (2H, ABq, J=12 Hz, 2-H), 5.02 (lH, d, J=4 Hz, 6-H), 6.01 (lH, d-d, J=4 and 6 Hz, 7-H), 6.45 (lH, s, thiazole-H), 7.00 (lH, s, CHPh2), 7.1-7.7 (40H, phenyl-H).
) R. Bucourt et al., Tetrahedron, 34, 2233 (1978) . . . - ~..

3~

Example 59 Diphenylmethvl_7-~(Z)-2-(2-tritylaminothiazol-4-vl)-2-trit~lox~imino-acetamidol-3-ttripheny~hosphornaylide e)methyl-3-ce~hem-4-carboxYlate II R2a=Tr~
A mixture of diphenylmethyl 7-l(z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (9.9 g, 9.3 m moles) and NaI (11 g, 73 m moles) in acetone (100 ml) was stirred for 30 min at room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 ml), and the mixture was washed with aqueous 10% Na2S2O3 solution (50 ml x 2) and water. To the mixture waæ added triphenylphosphine (3.93 g, lS m moles) and the mixture was stirred for 3 hr at room temperature. After evaporation, the residue was triturated with isopropyl ethe.r and the precipitate was collected by filtration to give the phosphonium salt (14.2 g). It was dissolved in CH2C12 (100 ml) and the solution was washed with lN NaOH (ca. 50 ml) until the phosphonium salt was completely converted into the yield by monitoring with TLC (Merck silica gel 60 F25~, CHCl3-MeOH, 10:1). The organic layer was separated, washed with water and concentrated under reduced pressure. The residue was triturated with isopropyl ether to giqe 12.0 g (94%) of the title compound.
IR : vmaX (KBr) in cm 1 1760, 1740, 165Q, 1480.
UV : ~max (CH2Cl2) in nm (~) 310(9200) 388(16200).

' ~

Exam~le 60 Di~_envlmethyl 7-~(z)-2-(2-tritylaminothiazQl-4-vl)-2=

cephem-4-carbQxylate (VIII R2a=Tr, R3=oAc) A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(triphenylphosphoranylidene)methyl-3-cephem-4-carboxylate (2.58 g, 2 m moles) and acetoxyacetaldehyde ) (612 mg, 3 m moles) in dichlcromethane (10 ml) was stirred overnight at room temperature and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel (Merck silica gel 60, 50 g) and the column was eluted with toluene-ethyl acetate (9:1). Evaporation of the fractions containing the desired product gave 1.0 g (45%) of the title compound.
IR : v max (KBr) in cm 1 1780, 1730, 1680, 1520, 1220.
UV : ~ max (CH2Cl2) in nm (~) 305(12200).
NMR : ~ (CDCl3) in ppm 2.00 (3H, s, COCH3), 3.20 (2H, ABq, J=18 Hz, 2-H), 5.1 (lH, d, J-4 Hz, 6-H), 6.20 (lH, d, J=11 Hz, =CH), 6.48 (lH, s, thiazole-H), 6.95 (lH, s, CHPh2), 7.1-7.6 (40H, phenyl-H).

) J. Cor~et and C. Benezra, J. Org. Chem., ~, 1141 (1981) , .

Example 61 7-~(Z)-2-(2-Aminothiazol-4-vl)-2-hvdroxyiminOaCe~ idol-3-~(Z~-3-ace~oxy-1-prQpenyll-3-ce~hem-4-carkoxylic acid (Ia, R2=H. R3=oAc) A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(Z)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate 13.29 g, 2.94 ~ moles) and 85% formic acid (15 ml) was stirred for 2 hr at room temperature. To the solution was added conc. hydrochloric acid (0.6 ml) and the mixture was stirred for 2 hr. After evaporation of the solvent, the residue was triturated with isopropyl ether to give 1.2 g of a crude product, which was chromatographed on a column lS of C18-silica gel (20 mm x 200 mm) by eluting with 20%
MeOH. The fractions containing the desired product were combined and concentrated to a small volume under reduced pressure. Lyphilization of the concentrate afforded 412 mg (30%) of the title compound, melting at 180C (dec.).
Estimated purity 50%.
IR : vmaX (KBr) in cm 1760, 1620, 1530, 1370, 1240.
UV : ~max (P~ 7 phosphate buffer) in nm (~) 279(15300).
NMR : ~ (DMSO-d6l in ppm 2.00 (3H, s, COCH3), 4.50 (2H, d, J=8 Hz, CH2O), 5.15 (lH, d, J=4 Hz, 6-H), 6.30 (lH, d, J=12 Hz, =CH-), 6.65 (lH, s, thiazol-H), 7.00 (2H, B, NH2), 9. 40 (lH, d, J=8 Hz, 7-CONH), 11.30 (lH, s, =N-OH).

v~
~,~

; E mple 62 3-Acetoxyethyl 7-~(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminQace~aml.dQl-3-~(Zl-_-acetoxy-1-~ropenyl-3-cephem-4-carboxylate tIb, R2=H, R3=oAc. R4=AX
To a stirred solution of Ia (R2=H, R3=oAc) (280 mg, 0.6 m mole) in dry DMF (2 ml) was added at -5'C Na2CO3 (105 mg, 1 m mole) and a solution of 1-acetoxyethyl bromide (396 mg, 2.37 m moles) in DMF (2 ml) in three portions at 20-minute'intervals and the mixture was stirred for additional 10 minutes. After dilution with ethyl acetate, the solution was washed with water and concentrated under reduced pressure. Trituration of the residue with isopropyl ether gave 195 mg of the crude product, which was chromatographed on a column of silica gel (25 g). The column was eluted with chloroform containing 1 - 2 % methanol and the fractions containing the desired product were combined and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave 75 mg (23%) of the product, melting at 100C (dec ). Estimated purity 70%.
IR : vmaX (KBr) in cm 1 1780-1730, 1670, 1530, 1380, 1240.
UV : ~max (CH2Cl2) in nm (E) 249(17300) NMR : ~ (CDCl3) in ppm 1.0 (3H, d, J=5 Hz, CH-CH3), 2.03 (3H, s, COCH3), 2.05 (3H, s, COCH3), 5.10 (lH, d, J=4 Hz, 6-H), 6.30 (lH, d, J=12 Hz, =CH-), 6.95 (lH, s, thiazole-H).

38~i~
-lO7-Compound 33, ~ample 63 ?-[(Z)-2-(2-Aminothiazol-4-yl)-2-hydroxJyiminoacetamide]-3~[(E)-1-propenyl]-3-cephem-4-carboxylic acid (Ia(E), R2 = H, R3 = H) A mixture of crude VIII (R2a = Tr, R3 = H) containing 20 % of its E
isomer (9.2 g, 8.7 mmol) in 85 ~ HCOOH (60 ml) was stirred for 1 hr at room temperature and evaporated in vac_o. The residue was treated with 90 %-TFA (60 ml) for 1 hr at room temperature and poured into ice-water (300 ml). The insolubles were filtered off. The filtrate was chromatographed on a reverse phase column (Waters, prepPA~ C18, 300 ml) and the column was eluted with 20 % MeOH. The polar fractions were combined, concentrated in vacuo and the residue was triturated with isopropyl ether to give 1.15 g (33 %) of the Z isomer (Ia, R2 = R3 = H) and the less polar fractions gave 143 ~g (4 ~) of the title compound. mp >200 C (dec). IR ~max (KBr) cm~1 1760, 1660, 1630, 1530. W ~max (pH 7 phosphate buffer) nm (F) 223 (20000), 290 (21000). 1H NMR (D20) ~ 1.38 (3H, d, J=7.0 Hz)? 3.73 (2H, br.s), 5.30 (1H, br.s), 5.85 (1H, d, J=S.O Hz), 5.80-6.30 (1H, m), 6.57 (1H, d, J=16 Hz), 7.06 (lH, s~

Anal Calcd for C15H15N55S2 1-5H2: C 41.28, H 4.16, N 16.05, S 14.65 Found : C 41.46, H 3.60, N 15.86t S 14.83 -108~ 8~

Compound 40, Example 64 Pivaloyloxymeth~_7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate (Ib, R2 = H, R3 = OAc, R4 = PV) To an ice-cooled mixture of Ia (R2 = H, R3 = OAc) (170 mg, 0.36 m mol) and Na2C03 (20 mg, 0.19 mmol) in dry DMF (2 ml) was added pivaloyl-oxymethyl iodide (87 mg, 0.36 mmol) and the mixture was stirred for 10 min at the same temperature. Additional amount of pivaloyloxymethyl iodide (87 mg) and Na2C03 (20 mg) was added and the mixture was stirred for additional 10 min. The mixture was diluted with ethyl acetate, washed with water and evaporated under reduced pressure. Chromatography of the residue on a silica g81 column and elution with CHCl3-MeOH (1-2 %) gave the product as an amorphous powder. Yield 110 mg (52 ~). mp 95-100 C
(dec). IR ~max lKBr) cm~1 1780, 1740,1670,1530. UV ~max (EtOH) nm (E) 280 (11400). 1H NMR (CDCl3) ~ 1.20 (9H, s, t-Bu), 2.0 (3H, s, OAc), 3.45 (2H, s, 2-H), 4.50 (2H, d, J=7 Hz, CH20Ac), 5.10 (lH, d, J=5 Hz, 6-H), 5.3-6.0 (4H, m, 7-H, vinyl-H, CH20CO), 6.25 (1H, d, J=12 Hz, vinyl-H)9 7.0 (1H9 9, thiazole-H), 11.5 (1H, d, J=8 Hz, CONH) Compound 41, Example 6~

7-[(Z)_2-(2-Aminothiazol-4-yl)-2-hydrox,yiminoacetamido~-3-[(E)-3-acetoxy-1-propenylj-3-cePhem-4-carboxylic acid (Ia(E), ~2 = H, ~3 = OAc) a) Acylation To a solution `of 1-hydroxybenzotriazole (223 IDg, 1.44 mmol) and (2)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (1.06 gt 1.44 mmol) in THF (14 ml) was added DCC (300 mg, 1.44 mmol) and the mixture was stirred for 1 hr at 5 C. Diphenylmethyl 7-amino-3-[(E)-acetoxy-1-propenyl]-3-cephem-4-carboxylate (670 mg, 1.44 mmol) was added to the mixture. After stirring for 4 hr at ambient temperature, the reaction mixture was filtered, diluted with ethyl acetate (50 ml) and washed with water. Concentration of the organic layer gave an oil, which was chroma-tographed on a column of silica gel. Elution with toluene-ethyl acetate (10:1) gave 1.607 g (99 ~) of diphenylmethyl 7-[(Z)-2-(2-tritylaminothia-zol-4-yl)-2-trityloxyiminoacetamido]-3-~(E)-3-acetoxy-1-propenyl] 3-cephem-4-carDoxylate as an amorphous powder. IR vmax (KBr) cm~1 1770~
1730. 1H NM~ (CDCl3) ~ 2.0 (3H, s, OAc), 3.33 (2H, s, 2-H), 4.54 (2HJ
ABq, CH20Qc), 5.04 (1H, d, J=5 Hz, 6-X), 6.0 (1H, m3 vinyl-H), 6.02 (lH, dd, J=5 & 7 Hz, 7-H), 6.40 (1H, s, thiazole-H), 6.82 (lH, d, J=15 Hz, vinyl-H), 7.00 (lH, s, Ph2CH), 7.3 (25H9 s, Ph).

b) Deblocking A ~ixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(E)-3-acetoxy-1-propenyl)-3-cephem-4-carboxy-late (1.98 g, 1.75 mmol) in formic acid (20 ml) was stirred for 2 hr at room temperature. Conc. hydrochloric acid (0.16 ml, 1.92 mmol) was added 0- ~ 7~

to the mixture and the mixture was stirred for 1 hr at room temperature.
Filtration, and concentration of the filtrate, followed by trituration with IPE gave 975 mg of the crude product. Chromatography on a column of reversed phase silica gel and elution with 10 % MeOH in water and concentration of the fraction containing the desired product gave 418 mg (51 %) of the title compound as an amorphous powder. I~ vmax (KBr) cm~
1765, 17309 1650. W AmaX (pH 7 phosphate buffer) nm (e) 290 (23400).
lH NMH (DMSO-d6) 3 2.03 (3H, s, OAc), 3.65 (2H, ABq, 2-H), 4.61 (2H, ABq, CH20Ac), 5.15 (lH, d, J=5 Hz, 6-H), 5.75 (1H, dd, J=5 & 8 Hz, 7-H), 6.15 (1H, m, vinyl-H), 6.65 (1H, s, thiazole), 6.85 (1H, d, J=15 Hz, vinyl-H), .05 (2H, s, NH2).

Compound 44, Examp~6 6 6 Pivaloyloxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-h~ x,y~ noacetamido]-3-[(E)-3-acetoxy-1-propenyl1 3-ce~hem~4-carboxylate (Ib(E), R2 = H, R3 =
OAc, R4 = PV) To a cooled and stirred mixture of Ia(E) (22 = H, R3 = OAc) (200 mg, 0.43 mmol) and Na2C03 (22.7 mg, 0.22 mmol) in DMF (2 ml) was added pivalo-yloxymethyl iodide (91 mg, 0.43 mmol) and the mixture was stirred at 5 C
for 30 min. The reaction mixture was diluted with ethyl acetate (40 ml), washed with water and brine successively. The organic layer was dried over MgSO~ and concentrated under diminished pressure. The crude product was chromatographed on a column of silica gel. Elution ~ith CHCl3~MeOH
(1-3 %) gavR 123 mg (50 ~) of the product as an amorphous powder. I~ vmax (KBr) cm~l 3300, 2970, 1780, 1740. UV ~max (MeOH) nm (~) 296 (18500).
1H NMR (DMSO-d6) 3 1.22 (9H, s, t-Bu), 2.08 (3H, s, OAc), 3.60 (2H, s, 2-H), 4.66 (2H, ABq, CH20Ac), 5.06 (1H, d, J=5 Hz, 6-H), 5.85 (1H,dd, J=5 7 Hz, 7-H), 5.88 (2H, ABq, 4-C02CH2), 6.0 (1H, m, vinyl-H), 7.00 (1H, s, thiazole), 7.1 (1H, d, J=15 Hz, vinyl-H).

Compound 46t Example 67 Acetoxy~ethyl 7-[(Z)-2- 2-aminothiazol-4-yl)-2-methox~iminoacetamido]-3-[(Z)-3-acetoxx~1-propenyl]-3-cephem-4-carboxylate (Ib9 R2 = CH3, R3 = OAc, R4 = AM) To a cooled and stirred solution of 240 mg (0.5 mmole) of Ia (R2 CH3, ~3 = OAc) in 4 ml of dry DMF were added at O C K2C03 (13~ mg, mmol) and a solution of acetoxymethyl bromide (306 mg, 2 mmole) in DMF (2 ml) in four portions at 15 minute-intervals and the mixture was stirred at 0-5 C for additional 15 minutes. After dilution with 100 ml of ethyl acetate, the mixture was washed with water and a saturated NaCl solution, and dried over MgS04. After removal of the solvent, the oily residue was purified by chromatography on a silica gel column ~Merck, Kiesel gel 60, g). The column was eluted with chloroform and chloroform-methanol (50:1 - 20:1) successively. The fractions eluted with chloroform-methanol (50:1) were collected and evaporated. The residue was triturated with ether-n-hexane to gi~e 72 mg (26 ~) of the desired product, melting at 90-C (dec.) Estimated purity 80 ~. IR vmax (KBr) cm~1 1770, 1730, 1670, 1610, 1530, 1370, 1230, 1030. UV ~max (MeOH) nm ( E ) 230 (17000), 287 (13000). 1H NMR-(CDC13) ~ 2.02 (3H, s, OAc), 2.12 (3H, s, OCOCH3), 3.33 (1H, d, J=18 Hz, 2-H), 3.60 (1H, d, J=18 Hz, 2-H), 4.04 (3H, s, OCH3), 4.4-4.6 (2H, m, CH20COCH3), 5.12 (1H, d, J=4.5 Hz, 6-H), 5.38 (2H, br-s, NH2), 5.82 (2H, s, COOCH20Ac), 5.4-5.9 (lH, m, CH=CHCH2), 5.98 (1H, dd, J=8 & 4.5 Hz, 7-H), 6.29 (1H, d, J=ll Hz, CH=CH-CH2), 6.82 (lH, s, thiazole-H), 7.55 (lH, d, J=8 Hz, NH).

-113~ 86~

Compound 6~, EY~aT~lple 68 7~[( Z? -2-(2-A inothiazol-4-yl)-2-acetoxyiminoacetamido3-3-[(Z)-3-acetoxy-1-pro~1]-3-cephem-4-carboxylic acid tIa, R2 = Ac, R3 = OAc) a) Acylation To a mixture of (Z)-2-(tritylaminothiazol-4-yl)-2-acetoxyiminoacetic acid (1~95 g, 4.0 mmol) and 1-hydroxybenzotriazole (600 mg, 4.0 mmol) in THF (14 ml) was added DCC (824 mg, 4.0 mmol) and the mixture was stirred for 1 hr in an ice bath. Diphenylmethyl 7-amino-3-[(Z)-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate (1.30 g, 2.8 mmol) was added to the suspension and the mixture was stirred for 4 hrs at ambient temperature, filtered, and diluted with AcOEt (60 ml). The organic phase was washed with water, dried over MgS04, and concentrated under reduced pressure.
The residue was chromatographed on a column on silica gel (Wakogel C200, 80 g), which was eluted wi'.h toluene-AcOEt (6:1). Fractions which contained the product were combined and concentrated in vacuo to give 2.01 g (77 %) of diphel.ylmethyl 7-~(Z)-2-(tritylamlnothiazol-4-yl)-2-acetoxy-iminoacetamido]-3-[(Z)-3-acetoxy-1-propenyl)-3-cephem-4-carboxylate (VIII, R2a = Ac, R3 = OAc). IR ~max (KBr) cm-1 1780, 1730. 1H NMR tCDC13) 2.0 (3H, s, CH3CO), 2.15 (3H, s, CH3CO), 3.45 (ZH, ABq, 2-H), 4.20 (2H, ABq, CH20Ac), 5.12 (1H, d, J=5 Hz, 6-H), 5.70 (1H, m, 3-CH=CH), 5.90 (1H, dd, J=5 & 7 Hzl 7-H), 6.26 (1H, d, J=1? Hz, 3-CH=CH), 6.95 (1H, s, thiazole), 7.30 (25H, s, phenyl).

b) Deblocking A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-acetoxyilllinoacetamido]_3_[(Zj-3-acetoxy-1-propenyl]-3-cephem-4-carboxylate ~114~ 86~

(3.2 g, 3.43 mmol) in TFA (20 ml) and anisole (5 ml) was stirred for 1 hr at 5 C. Removal of the solvent followed by trituration with 100 ml of isopropyl ether gave 1.25 g of TFA salt. The crude product was purified by chromatography using a column of C18 Bondapak, which was eluted with water, 10 % MeOH in H20 and 20 % MeOH in H20, successively. Appropriate fractions were co~bined, concentrated in vacuo and lyophilized to afford 395 mg (23 %) o~ the title compound. IR vmax ~KBr) cm 1 3300, 1770, 1670. W ~max (pH 7 phosphate buffer) nm (~) 228 (20300), 284 (15300). 1H
NMR (DMSO-d6) 5 2.0 (3H, s, CH3CO), 2.15 (3H, s, CH3CO)t 4.51 (2H, ABq~
CH2~0Ac), 5.22 (1Ht d, J=5 Hz, 6-H), 5.60 (1H, m, 3-CH=CH), 5.80 (1H, dd, J=5 & 7 Hz, 7-H), 6.32 (lHt d, J=12 Hz, 3-CH=CH), 7.05 (1H, s, thiazole).

115~ 7~

Compound 65, Example 69 1-Acetoxyeth~l 7-[(Z)-2-(2-aminothiazol-4-yl)-2-acetoxyiminoaeatamido]-3-~(Z)-3-aeetoxy-1 prope ~ 3-eephem-4-carboxylate (Ib, a2 _ Ae, R3 = OAe, R4 = AX) To a solution of Ia (~2 = Ac, R3 = OAc, 248 mg9 0.49 mmol) in 25 ml of dry DMF was added Na2C03 (51 mg, 0.49 mmol) and 1-acetoxyethyl bromide (82 mg, 0.49 mmol) at -10 ~C. The mixture was stirred at 5 C for 30 min and 82 mg (0.49 mmol) of 1-acetoxyethyl bromide was added to the suspension. After being stirred for 30 min more, the reaction mixture was diluted with AcOEt (50 ml), wzshed with water (30 ml x 3) and brine, dried over MgS04 and evaporated under diminished pressure. The crude produet was purified by siliea gel chromatography eluted with 3 % MeOH in ehloro-form. Removal of the solvent from appropriate eluant followed by freeze-drying gave 157 mg (54 ~) of the title compound, mp 125 ~C (dec). IR vmax (KBr) em~1 3430, 3290, 1770, 1680. W ~max (pH 7 phosphate buffer) nm (~! 228 (21900), 287 (12700). 1H NMR (DMSO-d6) ~ 1.51 (3H, d, J=6 Hz, 4-COOCHCH3), 2.02 (3H, s, AcO), 2.06 (3H, s, AeO), 2.22 (3H, s, AeO), 3.47 (2H, br.s, 2-H), 4.46 (1H, d, J=6 Hz, 4-COOCHCH3), 4.55 ~2H, ABq, CH20Ac), 5.12 (1H, d, J=5 Hz, 6-H), 5.70 (1H, m, 3-CH=CH-), 5.95 (lH, dd, J=5 & 7 Hz, 7-H), 6.25 (1H, d, J=12 Hz, 3-CH=CH), 6.92 (1H, s, thiazole).

7~38~

Compound 88, Example 70 ~5-Meth~l-2-oxo-1,3-dioxolen-4-yl)-methyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1-propenyl~-3-cephem-4-carboxYlate (Ib, R2 = H, R3 = H, R4 = -CH2 ~ CH3 To an ice-cooled and stirred solution of Ib (R2 = H, R3 = H) (512 mg, 1.25 mmol) in DMF (2 ml) were added sodium carbonate (238.5 mg, 4.5 mmol) and a solution of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one (869 mg, 4.5 mmol) in DMF (6 ml) in three portions at 15 minute intervals. The mixture was diluted with ethyl acetate (50 ml), washed with water and brine, and dried over MgS04. The filtrate was concentrated in vacuo. The residue was dissolved in a small amount of chloroform and purified by a silica gel column chromatography. (Kiesel gel 60, 30 g~. The desired fractions eluted with a mixture of chloroform and methanol (30 : 1) were combined, and concentrated in vacuo to give 182 mg (29 ~) of the desired product.
mp 115-120 C (decJ. IR ~max (KBr) cm 1 1820, 1770, 1735, 1530, 1210, 1190. W ~max (EtOH) nm (~) 225 (sh19000), 287 (12000). 1H NM~ (CDCl3 +
D~O) ~ 1.62 (3H, d, J=6.o Hz), 2.18 (3H, s), 3.45 (2H, br, s), 4.68 (2H, s), 5.10 (1H, d, J=5.5 Hz), 5.50-5.90 (1H, m), 5.85 ~1H, d, J=5.5 Hz), 6.12 (1H, d, J=12 Hz), 6.95 (1H, s).

, -117~ 8~

Compound ~9~ ~xa~ple 71 t-Ethoxyc rbonyloxyethyl_7-[(Z)-2-(2-aminothiazol)-4-yl)-2-h~droxyimino-acetamido]-3-[(Z)-1-propenyl]-3-cephe3-4-carbox~late (Ib, R2 = H, R3 = H, R4 = CH3CHOCOOEt) To a stirred solution of Ib (R2 = H, R3 = H, 256 mg, 0.625 mmol) in DMF (2 ml) were added sodium carbonate (40 mg, 0.625 mmol) and a solution of Q-iododiethylcarbonate (183 mg, 0.625 mmol) in DMF (1 ml) at 0-5 C.
After the mixture was stirred for 20 min at 5 G, sodium carbonate (40 mg) and a solution of ~-iododiethylcarbonate (183 mg) were added and the mixture was stirred for 40 min. The mixture was diluted with ethyl acetate (50 ml), washed with water (50 ml x 2), dried over MgS04 and filtered. The filtrate was concentrated in vacuo . The residue was dissolved in a small amount of chloroform and purified by a silica gel column (Kiesel gel-60, 20 g). The desired fractions eluted with a mixture of chloroform and methanol (30 : 1) were combined and concentrated in vacuo to give 56 mg (17 %) of the desired product. mp 105-110 C. IR
v ax (KBr) cm~1 1760, 1525, 1370, 1270. UV ~max (EtOH) nm ( ) (20000), 286 ~11000). 1H NMR (CDCl3 + D20) ~ 1.33 (3H, t, J=7 Hz), 1.57 (3Hl d, J=5 Hz), 1~70 (3H, d, J=7 Hz), 3.45 (2H, br. s), 4.23 (2H, q, J=7 Hz), 5.10 (1H, d, J=5.0 Hz), 5.87 (lH, d, J=5.0 Hz), 5.50-6.00 (1H, m), 6.16 (1H, d, J=12 Hz), 6.92 (1H, q, J=5 Hz)j 7.00 (1H, s).

Claims

1. A compound of the formula wherein R1 is hydrogen or a conventional amino-protecting group, R2 is hydrogen, or alkanoyl having 2 to 4 carbon atoms, R3 is hydrogen, or lower alkanoyloxy having 2 to 3 carbon atoms, and R4 is hydrogen, or a physiologically hydrolyzable ester group.

2. A compound of the formula wherein R1 is hydrogen or a conventional amino-protecting group;
R2 is hydrogen, or alkanoyl having 2 to 4 carbon atoms, R3 is hydrogen, or low alkanoyloxy having 2 to 3 carbon atoms, and R4 is hydrogen, or a physiologically hydrolyzable ester group selected from pivaloyloxymethyl,1-(acetoxy)ethyl, or acetoxymethyl with provision that when R4 is hydrogen at least one of R2 and R3 is other than hydrogen.

3. The compound of claim 2 wherein R1 is hydrogen and R2 is hydrogen, or acetyl.

4. The compound of claim 3 wherein R2 is hydrogen.

5. The compound of claim 4 wherein R3 is hydrogen.

6. The compound of claim 5 wherein R4 is acetoxymethyl.

7. The compound of claim 6 which is acetoxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl) 2-(hydroxyimino)acetamido] 3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

8. The compound of claim 6 which is acetoxymethyl 7 .beta.-[(z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-prop-1-en-1-y]-3-cephem-4-carboxylate.

9. The compound of claim 5 wherein R4 is 1-acetoxyethyl.

10. The compound of claim 9 which is 1-acetoxyethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

11. The compound of claim 9 which is 1-acetoxyethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-prop-l-en-1-yl]-3-cephem-4-carboxylate.

12. The compound of claim 5 wherein R4 is pivaloyloxymethyl.

13. The compound of claim 12 which is pivaloyloxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

14. The compound of claim 12 which is pivaloyloxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-prop-1-yl]-3-cephem-4-carboxylate.

15. The compound of claim 4 wherein R3 is acetoxy.

16. The compound of claim 15 wherein R4 is hydrogen.

17. The compound of claim 16 which is 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid.

18. The compound of claim 16 which is 7.beta.-[(Z) 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid.

19. The compound of claim 15 whsrein R4 is acetoxymethyl.

20. The compound of claim 19 which is acetoxymethyl 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

21. The compound of claim 19 which is acetoxymethyl 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-3-acetoxyprsp-1-en-1-yl]-3-cephem-4-carboxylate.

22. The compound of claim 15 wherein R4 is 1-acetoxyethyl.

23. The compound of claim 22 which is 1-acetoxyethyl 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

24. The compound of claim 22 which is 1-acetoxyethyl 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- [(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

25. The compound of claim 15 wherein R4 is pivaloyloxymethyl.

26. The compound of claim 25 which is pivaloyloxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamindo]-3-[(Z)-3 acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

27. The compound of claim 25 which is pivaloyloxymethyl 7.beta.-[(Z) 2-(2 aminothiazol 4-yl)-2-(hydroxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem 4-carboxylate.

28. The compound of claim 3 wherein R2 is acetyl.

29. The compound of cliam 28 wherein R3 is hydrogen.

30. The compound of claim 29 wherein R4 is hydrogen.

31. The compound of claim 30 which is 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3[[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylic acid.

32. The compound of claim 30 which is 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylic acid.

33. The compound of claim 29 wherein R4 is acetoxymethyl.

34. The compound of claim 33 which is acetoxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

35. The compound of claim 33 which is acetoxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3 cephem-4-carboxylate.

36. The compound of claim 29 wherein R4 is 1-acetoxyethyl.

37. The compound of claim 36 which is 1-acetoxyethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2 (acetoxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

38. The compound of claim 36 which is 1-acetoxyethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

39. The compound of claim 29 wherein R4 is pivaloyloxymethyl.

40. The compound of claim 39 which is pivaloyloxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-prop-l-en-l-yl]-3-cephem-4-carboxylate.

41. The compound of claim 39 which is pivaloyloxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

42. The compound of claim 28 wherein R3 is acetoxy.

43. The comppound of cliam 42 wherein R4 is hydrogen.

44. The compound of claim 43 which is 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid.

45. The compound of claim 43 which is 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylic acid.

46. The compound of claim 42 wherein R4 is acetoxymethyl.

47. The compound of claim 46 which is acetoxymethyl 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

48. The compound of claim 46 which is acetoxymethyl 7.beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

49. The compound of claim 42 wherein R4 is 1-acetoxyethyl.

50. The compound of claim 49 which is 1-acetoxyethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

51. The compound of claim 49 which is 1-acetoxyethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3 cephem-4-carboxylate.

52. The compound of claim 42 wherein R4 is pivaloyloxymethyl.

53. The compound of claim 52 which is pivaloyloxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

54. The compound of claim 52 which is pivaloyloxymethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3 [(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4 carboxylate.

55. The compound of claim 1 wherein R4 is 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl.

56. The compound of claim 55 which is 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2 (acetoxyimino)acetamido]-3-[(Z)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

57. The compound of claim 55 which is 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-prop-1-en-1-yl]-3-cephem-4-carboxylate.

58. The compound of claim 55 which is 5-methyl-2-oxo-1,3-dioxolen-4-methyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(Z)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

59. The compound of claim 55 which is 5-methyl-2-oxo-1,3-dioxolen-4-methyl 7 .beta.-[(Z)-2-(2-aminothiazol-4-yl)-2-(acetoxyimino)acetamido]-3-[(E)-3-acetoxyprop-1-en-1-yl]-3-cephem-4-carboxylate.

60. A pharmaceutical antibacterial composition comprising an effective amount of a compound of claim 3 in association with a pharmaceutically acceptable substantially nontoxic carrier or excipient.

61. The use of a substance as claimed in claim 3 for the treatment of a bacterial infection in a mammal caused by an organism sensitive to said substance.

62. The process for preparing the compound of claim 1 which comprises reacting a compound of Formula XV

XV

wherein R5 is a group of the formula XVI

or a group of the formula XVII

wherein R1' is a conventional blocking group used in cephalosporin chemistry for amino groups, R2a is a conventional blocking group used in cephalosporin chemistry for hydroxy groups, alkyl having 1 to 4 carbon atoms, alkenyl or alkynyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, or alkanoyl of 2 to 4 carbon atoms, and R4 is a conventional blocking group used in cephalosporin chemistry for carboxyl groups, with an aldehyde of the formula wherein R3 has the same meaning as in claim 1, in an inert organic reaction medium chosen from dichloromethane, N,N'-dimethylformamide, isopropanol or a mixture thereof, optionally in the presence of lithium chloride, lithium bromide or lithium iodide, at a reaction temperature of between 0 deg. C and 25 deg.
C to provide a compound of the formula XVIII

and when R5 is a benzylideneamino group (XVI), selectively removing the said group and if desired, converting the 3-(Z) isomer to the 3-(E) isomer by photo-chemical reaction and introducing the group of the formula XVII to provide a compound of the formula XIX

and thereafter removing blocking groups R1', R2a, and R4 and, if desired, separating the 3-(Z) and 3-(E) isomers to provide the compound of the formula Ia wherein R2 and R3 have the same meaning as in claim 1 and, if desired, reacting the alkali metal salt or ammonium salt of Compound Ia with the halide of the formula R4b-X
wherein X is a halogen choosen from chloro, bromo or iodo, and R4b is pivaloyloxymethyl, 1-acetoxyethyl, acetoxymethyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl or a group of the formula XXI

wherein R6 is hydrogen or a conventional protecting group used in cephalosporin chemistry for amino groups, and if desired, removing the protecting group to provide the ester of the formula Ib wherein R2, R3 and R4b are as defined above.